β 3 -Adrenoceptor ligand development history through patent review

1. Introduction

2. Areas covered

3. Structure of b3-AR, molecular

determinants of its ligands and

7TD amino-acid--ligand-specific

interactions

4. Expert opinion

Review

b3-Adrenoceptor liganddevelopment history throughpatent reviewMaria Grazia Perrone & Antonio Scilimati††University of Bari, Dipartimento Farmaco-Chimico, Bari, Italy

Introduction: Stimulation of the b3-adrenoceptor (b3-AR) is thought to be a

valuable approach for the treatment of obesity, type 2 diabetes, heart failure,

frequent urination, preterm labor, anxiety and depression. Therefore, the

b3-AR is recognized as an attractive target for drug discovery. Simultaneous

activation of the b1- and b2-AR can cause undesirable side effects such as

increased heart rate and muscle tremors. Consequently, much effort has

been directed towards the design and development of selective b3-AR ago-

nists through original synthetic chemistry, extensive in vitro tests and detailed

preclinical investigations to various phases of clinical trials.

Areas covered: SciFinder� Scholar, PubMed, ISI web of KnowledgeSM, Espace-

net, ClinicalTrials and Google have been used as the main sources for retrieving

literature and patents filed since the discovery of b3-AR through to June 2010.

This review discusses the enormous efforts made by private and public research

laboratories to uncover b3-AR ligands and to prove their usefulness as drugs.

Expert opinion: Remarkable knowledge has been gained about the physio-

pathological role of the b3-AR to date. Many highly potent and selective

b3-AR ligands (agonists, antagonists and inverse agonists) have been discov-

ered; however, further investigations are still needed to identify novel com-

pounds acting as b3-AR ligands in order to adequately treat the diseases in

which b3-AR is involved.

Keywords: anxiety and depression, apoptosis, arylethanolamine, aryloxypropanolamine,

cachexia, colon cancer, heart failure, intestine disorders, metabolic syndrome,

obesity and type 2 diabetes, overactive bladder, preterm labor,

structure--activity relationship, b3-adrenoceptor

Expert Opin. Ther. Patents (2011) 21(4):505-536

1. Introduction

b3-Adrenoceptor (b3-AR) was uncovered at the beginning of 1980 as a b-AR sub-type, initially called atypical b-AR, different from b1- and b2-ARs [1,2]. The impor-tance of the b3-AR has increased more since the amino-acid sequence of the humanreceptor was elucidated in the late 1980s. The b3-AR has ~ 50% homology to theb1- and b2-AR subtypes.

A large number of papers and patents have been published (Figure 1) and filed(Figure 2), respectively, during the last 30 years reporting successes in the discoveryof agents that stimulate the b3-AR. Despite several achievements, there remains aneed to develop a selective b3-AR agonist, which has ‘in vivo’ minimal agonistactivity against b1- and b2-ARs.

Figures 1 and 2 clearly show that the interest in development of b3-AR ligandsis declining in recent years. This is mainly due to the fact that most of the com-pounds identified as b3-AR stimulants in animals failed in clinical trials. Hence,at present much more efforts are needed, mainly to find both the rationale

10.1517/13543776.2011.561316 © 2011 Informa UK, Ltd. ISSN 1354-3776 505All rights reserved: reproduction in whole or in part not permitted

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beyond all the available published data obtained by usinganimal models and how they can correctly translateto humans.Renewed interest could also be raised from recent studies

that show that mouse b3-AR of ventricular cardiomyocytesis localized at the nuclear membrane to mediate transcrip-tion [3]. The pharmacological stimulation of b3-ARs innuclear preparations from the heart was linked to increasedgene transcription [4]. The mechanism required for nuclearlocalization of cardiac b3-AR is currently unknown.Earlier, b3-AR was considered a valuable therapeutic target

by most pharmaceutical industries worldwide because it wasdirectly linked to obesity.In general, agonists of b-ARs promote the activation of

adenylyl cyclase. Activation of b1-AR triggers increases inheart rate and the activation of b2-AR induces relaxation

of skeletal muscle tissue which produces a drop in bloodpressure. Activation of b3-AR is known to stimulate rodentlipolysis (breakdown of adipose tissue triglycerides to glyc-erol and free fatty acids) and metabolic rate (energy expen-diture), and thereby promote the loss of fat mass.Compounds that stimulate b3-AR (i.e., CL 316,243) are,therefore, useful as anti-obesity agents and can also beused to increase the content of lean meat in edible ani-mals [5]. b3-AR-mediated lipolysis is mainly a rodent phe-nomenon [6]. b3-AR plays a small role, if any, in humanadipocyte tissue, where it can be detected at the mRNAlevel. Functional studies on lipolysis in humans based onreliable tools have implicated mainly b1- and b2-ARs [7,8].In addition, b3-AR agonists have anti-diabetic activity byimproving glycemic control, insulin sensitivity and glucosetolerance in rats. On the other hand, all the investigationsaimed at proving the usefulness of b3-AR stimulants asanti-obesity and anti-type 2 diabetes in humans have failed.

b3-AR has been also considered as a therapeutic target forheart failure, ulcero-inflammatory disorders of gut and itsneoplasia, overactive bladder (OAB), preterm labor, anxietyand depression [9].

By using pharmacological approaches, it was determinedthat b-adrenergic relaxation of the cattle iris muscles wasmediated by a mixed population of b-ARs, with the pre-dominance of b3-AR [10]. b3-AR protein was also detectedin lysates of human retinal endothelial cells. In addition, itwas hypothesized that b3-AR might play a part in the pro-liferation and migration of human culture retinal endothelialcells [11].

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Figure 1. Number of papers dealing with b3-AR published till June 2010 in the field of medicinal chemistry, biochemistry and

pharmacology.

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2006/2010

Figure 2. Number of patents filed till June 2010 claiming the

b3-AR as a therapeutic target.

b3-Adrenoceptor ligand development history through patent review

506 Expert Opin. Ther. Patents (2011) 21(4)

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It is also noteworthy that b3-ARs were found on isolatedcanine pulmonary arterial rings under isometric conditionsin vitro and their stimulation induced a cAMP-dependent vaso-dilatation [12]. The putative presence of b3-AR in peripheralmicrovascular muscle was studied in dogs throughmeasurementof cutaneous blood flow and skin temperature changes, and theirstimulation induced vasodilatation [13]. In anesthetized rhesusmonkeys, a vasodilator effect was observed also in the cutaneousand fat tissues and led to a decrease of the blood pressure and areflex increase in cardiac frequency [14]. b3-ARs were also foundon rat endothelium of the thoracic aorta and act synergistic withb1- and b2-ARs in mediating vascular relaxation by activation ofNO synthase and NO production, with increase of cGMP [15].Relaxation of aorta through b3-AR proved to be independentof the stimulation of Gi/o proteins, but was given by the activa-tion of some potassium channels: KCa, KATP and Kv [16]. In vitrostudies showed that b3-AR agonists induced a relaxation of thecarotid artery in rats, which was not antagonized by proprano-lol [17]. In humans, b3-AR was found in the endothelium ofthe internal mammary artery producing NO-induced vasodila-tation, a possible practical implication in coronary artery bypasssurgery [18]. b3-ARs were also found in the human coronaryarteries using reverse transcription-PCR and immunostaining.They mediated adrenergic vasodilatation by two mechanisms:increase in the NO synthesis and cellular hyperpolarization(through K channels-calcium-dependent) [19-22].

2. Areas covered

2.1 b3-AR as a therapeutic targetIt has been found that b3-AR agonists are potentially usefulagents for the prevention or treatment of obesity, hyperglyce-mia, diseases caused by intestinal hypermotility, pollakiuria,urinary incontinence, anxiety and depression, diseases causedby biliary calculi or hypermotility of biliary tract, and heartfailure. Consequently, studies have been made to develophighly potent and selective b3-AR stimulants, but no ARligand has yet been sold [23,24]. Nevertheless, many b3-AR ago-nists reached Phase I--III clinical trials (i.e., amibegron bySanofi-Aventis, solabegron by GlaxoSmithKline, mirabegronby Astellas Pharma, ritobegron by Kissei Pharmaceutical).

2.2 Obesity, type 2 diabetes and metabolic syndromeThe current preferred treatment for obesity as well astype 2 non-insulin-dependent diabetes is diet and exercise,with a view toward weight reduction and improved insulinsensitivity [25]. Patient compliance, however, is usually poor.The problem is compounded by the fact that there are cur-rently no approved medications that adequately treat obesity.

One therapeutic opportunity that has been recognizedinvolves the relationship between AR stimulation and anti-hyperglycemic effects. Compounds which act as b3-AR ago-nists have been shown to exhibit a marked effect on lipolysisand thermogenesis, and serum glucose levels in animal modelsof type 2 diabetes.

It is clear that though the b3-AR plays a key role in medi-ating thermogenesis in rodents, and specific b3-AR agonistsincrease metabolic rate and lead to weight loss in obeserodents, the role of b3-AR in humans remains controversial.In human newborn perirenal brown adipose tissue (BAT),the levels of b1-, b2- and b3-AR mRNA were found to be28, 63 and 9%, respectively, of the total AR mRNA; however,in adult human abdominal white adipose tissue (WAT), nob3-AR mRNA was detected by northern blot analysis. In aseparate study, using a sensitive and specific RNase protectionassay without previous PCR amplification, b3-AR mRNA wasdetected in human WAT, gall bladder and small intestine,confirming an earlier report. It was found to a lesser extentin stomach and prostate [26].

The b3-AR appears to play also a key role in the action andregulation of leptin.

This hormone, the product of the ob gene, is secreted byadipocytes and, acting via the hypothalamus, inhibits foodintake and stimulates metabolic rate. Leptin-induced activa-tion of the sympathetic nervous system and the resultantb3-AR-mediated thermogenesis in BAT may be responsiblefor the latter effect.

Selective b3-AR agonists effectively lead to an increasein insulin sensitivity and are, hence, useful in treatingtype 2 diabetes and other ailments implicated by the b3-AR.

In addition, very recently, it has been reported that theanti-diabetes effect of b3-AR agonists CL 316,243 and SR58611A seems due to the mechanistic link between the freefatty acid receptor (GPR40) and adrenergic signaling inadipose tissues and pancreatic b-cell function [27].

Accordingly, several drug discovery programs have beentaken to the point of human proof-of-concept studies (includ-ing Astellas, GlaxoSmithKline or Merck) for indications suchas obesity and type 2 diabetes, but they all failed and thecorresponding programs have been discontinued acrossthe industry.

On the contrary, b3-AR blockade might constitute anotherpossible therapeutic indication of b3-AR, particularly when itis necessary to inhibit fatty acid release from visceral adiposetissue aimed at improving some of the metabolic abnormali-ties associated with the high ‘portal’ fatty acid flux, as forobese subjects with signs of the metabolic syndrome [28].

2.3 Wasting conditionThe use of a substituted 1,3-benzodioxole (CL 316,243) wasfound to reduce a wasting condition [29].

Various pathologies and metabolic states in a subject canproduce a wasting condition that is characterized, in part, bya progressive loss of body, organ or tissue mass such as a lossof bone or muscle mass or a decrease in tissue protein.A wasting condition can occur as a result of pathology suchas cancer, or can be due to a physiologic or pathologicmetabolic state.

A wasting condition, if unabated, can have dire healthconsequences detrimental to an individual’s health. The severe

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Expert Opin. Ther. Patents (2011) 21(4) 507

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wasting or cachexia associated with cancer, for example, canprolong patient convalescence and decrease the patient’squality of life.Three general approaches have been utilized to reduce a

wasting condition in a subject. One approach has been to alterthe systemic stress response caused from acute injury or illnessby manipulating the signals mediated by cytokines or lipids,which are involved in regulating the stress response. Anotherapproach to reduce a wasting condition has been to adminis-ter supplemental nutrition. Nutritional supplementation hasbeen used in combination with the administration of anabolicagents, particularly for body mass loss due to acute illness, dis-use deconditioning and cachexia. Among various anabolicagents, b-AR agonists have been used in the combined modal-ity protocol. The b2-AR agonists clenbuterol and salbutamolare anabolic agents that can reduce weight loss, particularlyloss of muscle mass and bone density [30]. However, b2-ARagonists can produce undesirable effects, including increasedheart rate, decreased blood pressure or muscle tremor, in atreated subject. These agents also can produce undesirablebehavioral changes. Thus, a need exists to identify pharma-ceutical agents that effectively reduce a wasting condition ina subject without producing significant adverse side effects.Tisdale has demonstrated the involvement of b3-AR in the

biochemical pathway of cachexia [31].b3-AR antagonists [32] and even better inverse agonists [33,34]

would also be useful to prevent or control cachexia, a para-neoplastic condition consisting of remarkable body weightloss. In cachectic oncologic patient urines, very high levels ofa Zn-a2-glycoprotein known as lipid-mobilizing factor(LMF) and several cytokines (i.e., TNF-a) were found, andit seems that at least in part the adipose tissue loss (~ 30%of pre-illness stable weight at diagnosis) is induced fromb3-AR, activated by LMF.It should be emphasized that most of the functional avail-

able data mentioned above are largely based on animal studiesand, therefore, unlikely to be predictive for humans.

2.4 Heart failureIn the human heart, b3-AR coupling to a Gi-protein producesnegative inotropic and positive chronotropic effects, via theactivation of eNOS and the subsequent NO release that deter-mines a consistent cGMP increase. In the failing human heart,there is a sustained release of catecholamines that induces a pro-gressive downregulation of b1- and b2-ARs, due to their desen-sitization by protein kinase A-mediated phosphorylation,whereas b3-AR population grows or remains unchangedbecause it lacks the phosphorylation site responsible for desen-sitization and internalization of the other two b-AR subtypes.This may lead to an imbalance of the cardiac b-AR populationwith an excessive promotion of b3-AR-negative inotropiceffect, which results in a potentially fatal reduction ofcardiac contractility. As a consequence, b3-AR becomes a newtarget for treatment and prevention of cardiac failure [35-38].Stimulation of b3-AR subtype inhibits cardiac contractility,

thus opposing the response of b1- and b2-ARs. In failing heart,b3-AR is upregulated. It probably serves as a buffer, exerting a‘rescue’ function from the effects of high plasma levels of cate-cholamines, as those observed in hyperadrenergic states includ-ing heart failure. On disease progression, b3-AR upregulationmay produce a depression in contractility, which exacerbatesheart failure [36,39,40]. Hence, selective b3-AR agonists shouldserve in the early stage of heart failure, whereas highly selectiveantagonists/inverse agonists might be useful in the advancedstage of the disease [33,34].

2.5 Overactive bladderThe bladder base and urethra contain a high density ofa-ARs, stimulation of which gives rise to contractions; blad-der body also contains a high density of b-ARs, whose stimu-lation determines relaxation and urine storage; b3-AR mRNAwas also detected in human detrusor muscle [41,42] and inhuman urinary bladder urothelium [43] where it was foundto be more expressed than b1- and b2-AR mRNA.

The normal physiological contraction of the urinary blad-der is mostly mediated by muscarinic receptors, primarilyM3 subtype. Bladder relaxation, required for urine storage,is predominantly, if not exclusively, mediated by b3-AR sub-type [44,45]. An excessive stimulation of contraction or areduced relaxation of the detrusor smooth muscle during theurine storage phase may determine OAB, a syndrome charac-terized by urinary frequency, nocturia and urgency inconti-nence. Several studies were carried out to demonstrate theb3-AR involvement in urinary frequency and identify potentrelaxant agents of the human detrusor muscle as an alternativeto the classical treatment with muscarinic receptor antagonistsendowed with poor therapeutic index [46]. The expectedfuture use of b3-AR agonists is the treatment of urinary blad-der dysfunction, even if their possible adverse events related tocardiac function remain to be determined from clinical stud-ies [47]. b3-AR agonists such as mirabegron, ritobegron andsolabegron have been deeply investigated in human OABclinical trials.

In particular, two major clinical studies have beenpublished on mirabegron [25,27], ritobegron has been with-drawn from development as it did not reach its primaryefficacy end point in pivotal studies, and solabegron nevermade it beyond Phase II and is no longer pursuedby GlaxoSmithKline.

2.6 Intestine disordersb3-ARs are widely distributed in the gastrointestinal tract ofseveral species, including humans [9,33,48,49]. In particular,they are expressed in gut vascular and nonvascular smoothmuscle where they mediate relaxation and are probablyinvolved in the control of blood flow.

b3-AR modulates colonic motility. In particular, isolatedhuman colon elevated tone and spontaneous contractionsare reduced and inhibited, respectively, by b3-AR agonistssuch as SR 58611A or CGP 12177A [50]. The relaxing effect



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of b3-AR agonists on gut smooth muscle explains the increasein compliance (i.e., the ability of the gut to relax on applica-tion of a distending stimulus) and may turn out to be an use-ful approach in some functional gut disorders (e.g., functionaldyspepsia), where decreased gastric accommodation is apathophysiological feature [51].

In addition, activation of b3-AR by their agonists leads toan inhibition of cholinergic contractions and evokes somatos-tatine release, resulting in a decrease of intestinal motility andsecretion, and inducing analgesia [52]. Moreover, b3-AR ago-nist administration confers gastroprotection in several modelsof gastric ulcer [53,54], an effect that may be due to increasedblood flow by vasodilatation and/or relaxation of the muscu-laris externa mediated by b3-ARs. Recently, it has been shownthat SR 58611A ameliorates dinitrobenzenesulfonic acid-induced colitis in rats and downregulates the biosynthesis ofinflammatory cytokines. In this context, the finding ofb3-ARs in rat [55] and human [26,56] myenteric neurons andin nerve fibers clarifies the role of these receptors as a potentialtherapeutic target for gut inflammatory disease.

However, in human OAB clinical studies constipation is arelevant side effect. This raises doubts on the validity of theconcept of using such compounds for gastrointestinal motilitydisorders. This published clinical evidence overrules theanimal data [57].

2.7 Colon cancerA modified b-adrenergic function associated with proliferativealterations of numerous cancer cell lines seems to be involvedin tumor cell proliferation and migration and metastasis for-mation which, therefore, seem to be involved in the mostimportant aspects of malignant phenotype. Pharmacologicalmodulation of b-ARs affects tumor cell growth in severalexperimental systems, and inhibition of metastasis formationby b-ARs antagonists in in vivo models has been ascer-tained [58]. Initial epidemiological studies provided evidencethat b-blockers can reduce cancer incidence, thus suggestingtheir possible role also in cancer prevention. A preliminarystudy, performed on human colon cancer and normal sur-rounding mucosa aimed at investigating the b1-, b2-, andb3-AR gene expression, showed significant difference ofb3-AR mRNA levels between normal mucosa and cancer tis-sue. A twofold higher expression of b3-AR mRNA in cancertissue than normal one was found, thus suggesting a b3-ARpossible involvement in the human colon tumor onset andprocessing [59].

2.8 Preterm labor, IUGR and pre-eclampsiaThe management of premature birth still remains unsatisfac-tory because of the relative lack of efficiency and/or safety ofcurrent tocolytic agents. Thus, new utero-relaxant drugsdeprived of important maternal and fetal side effects areneeded. b3-AR is a potential new target for tocolytic drugsbeing present and functional in human pregnant andnon-pregnant myometrium, and able to reduce in vitro

spontaneous contractions of myometrial strips, via a cAMP-mediated pathway. Furthermore, b3-AR is predominant overthe b2-AR in human myometrium and its expression isincreased in near-term myometrium, compared to non-pregnant myometrium [60]. Finally, contrary to b2-AR, thehuman myometrial b3-AR is resistant to long-term agonist-induced desensitization. Hence, b3-AR agonists may have apharmacological use in the preterm labor clinical manage-ment. As a confirmation of this, BRL 37344, a b3-AR agonist,induces relaxation of human myometrial contractions withsimilar potency to that of ritodrine (b2-AR agonist), themost commonly used tocolytic agent [61], and reduced cardio-vascular side effects [62]. Further studies are needed, by usingselective and more potent b3-AR agonists, to confirm theiruse to delay human preterm labor.

Studies on apoptosis and proliferation in uterine cell turn-over during the estrous cycle and early pregnancy indicatedthat uterine cell apoptosis and proliferation patterns are highlyordered cell-specific phenomena that play an important rolein maintaining the pregnancy-associated uterine changes. Inparticular, they indicate that caspase-3-mediated cell apopto-sis may be fundamental in initiating the implantation processin hamsters and mice [63,64].

The first topic of interest for apoptosis in the field of preg-nancy is the pathologies of the placenta. Indeed, apoptosis ofvillous trophoblast is upregulated in both of the common preg-nancy diseases related to the placenta, namely, intrauterinegrowth restriction (IUGR) and pre-eclampsia [65-68]. As it hasrecently been shown that apoptotic nuclei are more abundantin fetal growth restricted placentas compared with control pla-centas [69], inhibiting apoptosis can be considered as a promis-ing approach to treat or prevent IUGR or pre-eclampsia.Spontaneous preterm labor is one of the largest causes of pre-term birth which in turn is the most frequent cause of infantdeath in Western countries [70]. A significant proportion ofmany cases of spontaneous preterm labor are caused by genitaltract infection or chorioamnionitis [71]. Charpigny et al. showedthat apoptosis-associated genes were upregulated during partu-rition [72]. Apoptotic cell death can be initiated by two alterna-tive convergent pathways: the extrinsic pathway, which ismediated by cell surface death receptors, and the intrinsic path-way, which is mediated by mitochondria [73]. In both pathways,cysteine aspartyl-specific proteases (caspases) which cleave cellu-lar substrates are activated, and activation of the effectorcaspase-3 is important for the execution of apoptotic cell death.The Bcl-2 (B-cell lymphoma 2) family members play a centralrole in the regulation of apoptosis. The multidomain proapop-totic proteins Bax (Bcl-2-associated X protein) and Bcl-2-asso-ciated K protein together constitute a requisite gateway toapoptotic cell death because cells doubly deficient for these pro-teins are resistant to several different intrinsic death stimuli [73].Therefore, Bax, Bcl-2 and cleaved caspase-3 are widely used toassess apoptosis.

Western blot experiments revealed that the selectiveb3-AR agonist ethyl-4-{trans-4-[((2S)-2-hydroxy-3-{4-hydroxy-

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3-[(methylsulfonyl)-amino]phenoxy}propyl)amino]cyclohexyl)}benzoate hydrochloride (compound A [74]) is able to anta-gonize lipopolysaccharide (LPS)-induced changes in cleavedcaspase-3 expression in a concentration-dependent manner.Furthermore, LPS-induced activation of the mitochondrialpathway of apoptosis, as expressed by Bax and Bcl-2 proteinup- and downregulation, respectively, is antagonized in aconcentration-dependent manner. Compound A had no effectby itself on cleaved caspase-3, Bax and Bcl-2 expression intissues not stimulated with LPS.The effect of compoundA on caspase-3 overexpression was, at

least partially, explained at a transcriptional level as quantitativereal-time reverse transcription-PCR which showed that b3-ARactivation was associated with a decreased level of caspase-3 tran-scripts. Finally, compound A decreases IL-6 and IL-8 in aconcentration-dependent manner, even though the effect wasstatically significant only for IL-8. Compound A did not havean effect by itself on IL-6 and IL-8 release in tissues not stimu-lated with LPS. Altogether, these results demonstrate that com-pound A, a b3-AR agonist reverses an LPS-induced apoptosisand cytokines production in human near term myometrium.Thus, b3-AR agonists might be suitable to prevent or treat

IUGR or pre-eclampsia and preterm premature rupture of fetalmembranes by inhibiting apoptosis in pregnancy-related tissues(uterus, placenta and fetal membranes), being able to controlthe apoptotic pathways due to fertility disorders and genitaltract infection (chorioamnionitis) [75].

2.9 Intrahepatic resistance and portal hypertension

in liver cirrhosisIncreased intrahepatic resistance and splanchnic blood flowcause portal hypertension in liver cirrhosis. Nonselectiveb-AR antagonists (i.e., propranolol) have beneficial effectson hyperdynamic circulation and are in clinical use. In cirrho-sis of humans and rats, mRNA and protein b3-AR expressionis markedly increased in hepatic and splanchnic tissues. Incirrhotic rats, b3-AR agonists such as CGP 12177A andBRL 37344 lower intrahepatic resistance and portal pressure.On the other hand, b3-AR pharmacological stimulation bytheir agonists, in combination with nonselective b-AR block-ers, results in a stronger beneficial effect on portal pressure incirrhosis than nonselective b-AR blockers alone. By contrast,in the splanchnic vascular compartment the effect mediatedby b3-AR is minor.In conclusion, there is a marked hepatic and mesenteric

upregulation of b3-ARs in human cirrhosis and animal mod-els of cirrhosis. Thus, the b3-AR may represent a new targetfor the therapy of portal hypertension in cirrhosis [76].

2.10 Anxiety and depressionAmong the three b-AR subtypes that mediate the action ofnoradrenaline, little is known about the central role of the GS-protein-coupled b3-AR subtype. The receptor is positively cou-pled to adenylyl cyclase and mainly present in peripheraltissues. In the human brain, b3-AR mRNA has been found in

small quantities. Transcripts were recently detected in rat andmouse brain sub-regions such as cortical areas, hippocampusand amygdala. These brain regions have been largely describedto participate in the control of emotions and are considered tobe the main target for current treatments of depression thatenhance serotonergic and/or noradrenergic transmissions. Thecharacterization of the functional role of theb3-ARs inmediatingemotional behaviors was made possible with the availability ofthe first selective orally active and brain-penetrantb3-AR agonist,amibegron (SR 58611A by Sanofi-Aventis), which has beenshown to display broad anxiolytic and antidepressant-like effectsin a variety of models in rodents [77,78].

For instance, amibegron attenuated physical consequences ofa chronic exposure to unpredictable stress using the chronicmild stress, a model of depression with good phase and predic-tive validity, suggesting antidepressant-like properties of thecompound. Indeed, the progressive degradation of the coatstate (loss of fur and dirty fur) induced by the application ofmild stressors across several weeks is blocked by both amibe-gron and prototypical selective serotonin reuptake inhibitorsantidepressant fluoxetine. The mechanism whereby amibegronproduces its effects is not fully elucidated. Recently, argumentsin favor of an involvement of central serotonergic and norad-renergic systems in mediating the effects of amibegron havebeen provided. However, in the absence of a selective and cen-trally acting b3-AR antagonist, the contribution of b3-ARs inthe antidepressant-like actions of amibegron cannot be phar-macologically addressed. An alternative method of explorationof the b3-AR-mediated specificity of amibegron would be toadminister the compound in knockout animals or more simplyby using the known b3-AR inverse agonists [33].

Amibegron seems to lack important side effects such as thetachycardia or alteration of locomotor activity [77,79]. Theeffects of amibegron mediated by the b3-AR suggests thatthis receptor subtype may represent an alternative target fornovel antidepressant drugs. Phase III clinical trials onSR 58611A for the treatment of anxiety and depressionhave been terminated [80] (on 31 July 2008, Sanofi-Aventisannounced that it had decided to discontinue the amibegronprogram due to hepatic dysfunction side effect. The studywas retrieved on 9 March 2009) and a further developmentreport is awaited.

3. Structure of b3-AR, moleculardeterminants of its ligands and7TD amino-acid--ligand-specific interactions

3.1 b3-AR structure and 7TD amino-acid--ligand-

specific interactionsAmong different species, the comparison of b3-ARs reveals ahigh degree of sequence homology: ~ 80 -- 90% amonghuman, bovine, rodent and canine models.

The human b3-AR is composed of a single 408 amino-acidresidue peptide chain belonging to the family of GPCRs. Ithas hydrophobic stretches of about 22 -- 28 residues forming



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seven transmembrane (TM) segments. The TM regions arelinked with three intracellular and three extracellular loops.At least four of the seven transmembrane domains (7TDs)are essential for ligand binding. The crucial amino acids thatare involved were identified by site-directed mutagenesis andphotoaffinity labeling. Asp117 in TM3 is the residue foundto be essential for binding all biogenic amines. The acidicside chain most likely forms a salt bridge with the basic groupof the ligand. Indeed, substitution of this residue in thehuman b3-AR completely suppresses agonist binding.Ser169 in TM4 is thought to form a hydrogen bond withthe hydroxyl of the ethanolamine side chain. Ser209 andSer212 in TM5 are thought to form hydrogen bonds withthe hydroxyl groups of the catechol moiety. Also, Phe309 inTM6 is involved in a hydrophobic interaction with the aro-matic ring of catecholamines. Asp83 (TM2) and Tyr336(TM7) are likely to be more important for signal transmissionto Gs. The Gs interaction site on b3-AR is situated in theintracellular region, mainly the membrane proximal regionsof the second and third (i2, i3) intracellular loops and thecarboxy-terminal domains. Deletion of small segments ofthe amino terminal and carboxy terminal regions of thei3 of the b3-AR uncouples the human receptor from adenylylcyclase on agonist stimulation [81].

3.2 b3-AR ligand selectivityThe high sequence similarity of b1-, b2- and b3-ARs, particu-larly in the TM helical bundle domain (69% sequence identityand 87% identity plus conservative substitution for b1- vsb2-AR; 65% identity and 87% identity plus conservative sub-stitution for b1- vs b3-AR; 60% identity and 83% identityplus conservative substitution for b2- vs b3-AR), suggests thatthey must possess quite similar 3D structures. The residues lin-ing the binding site region of the three receptors are nearlyidentical (75 -- 85% sequence identity and 95 -- 100% identityplus conservative substitution), so the binding site pockets ineach receptor subtype must also have extremely similar struc-tures. Despite the extremely high sequence similarity for allthree receptor subtypes, there is emerging evidence that theb3-AR may bind ligands somewhat differently than b1- andb2-ARs. A number of ligands that behave as antagonists forb1- and b2-ARs are partial to full agonists for b3-AR. Addition-ally, a number of ligands which exhibit impressive b3-AR selec-tivity has been developed, confirming that exploitabledifferences do exist between these receptors [82].

Most b3-AR selective agonists do not share adrenaline’s cat-echol ring, but instead have a pyridine or m-chlorophenyl ring,or in some cases, a more extensive heteroaromatic ring systemreminiscent of b1-AR antagonists (b-blockers).

Support for the above binding site interactions is providedby massive studies of structure--activity relationships on cate-cholamines. These have emphasized the importance of havingboth the alcohol group and the ionized amine in the sidechain, and also of the absolute configuration (R)/(S) of thearylethanolamine/aryloxypropanolamine stereogenic center.

Some of the evidences supporting these conclusions are asfollows:

. the secondary alcohol is involved in stereospecific hydro-gen bonding interactions. It is important but not essen-tial because compounds lacking the hydroxyl group(e.g., dopamine) retain some activity.

. ethanolamine/propanolamine nitrogen replacementwith carbon results in the reduction of the activity. Pri-mary and secondary amines have good adrenergic activ-ity, whereas tertiary amines and quaternary ammoniumsalts do not. b3-AR activity has been showed for only afew tertiary amines in which the nitrogen atom is partof a piperazine ring in an aryloxypropanolamine [83].

. phenyl substituents are also important and the twohydroxyls can be replaced by other groups.

. N-alkyl substituent has a role in receptor selectivity:adrenaline has the same potency for both a- andb-ARs, whereas noradrenaline has a greater potencyfor a- than b-ARs. Increasing the size of the N-alkylsubstituent determines the loss of potency at a-ARsand positively enhanced the potency towards b-ARs.The presence of a bulky N-alkyl group is beneficial tob3-AR activity. These results indicate that b3-ARshould have a larger hydrophobic pocket than b1-and b2-ARs into which a bulky alkyl/aryl/alkyarylgroup can fit. Besides, b3-AR activity is still exalted ifeither the R¢ or R¢¢ group bears polar and/or ionizablefunctionalities including ureas, acylamides, sulfona-mides and sulfonic, phosphonic, and carboxylic groups(Figure 3) [33,83-91].

3.3 Stereospecific interactions and biological activity

relationshipTraditional b-AR ligands show higher affinities and higherstereospecificity indices towards human b3-AR than at mouseor rat receptors [92].

In addition, b3-AR displays a different degree of stereo-specificity for several known traditional b-AR ligands. Itshows both a lower degree of stereoselectivity for agonistssuch as isoprenaline and noradrenaline and a higher degreeof stereoselectivity for antagonists (i.e., propranolol) thanb1- and b2-ARs. There is no simple, consistent explanationfor stereoselectivity of b-adrenergic agonists and antagonists.An attempt to rationalize the findings strongly suggests thata single, static 3D model is not adequate to explain stereose-lective ligand binding (or other ligand-binding characteris-tics) for all b-adrenergic ligands. This is quite consistentwith the idea that GPCRs undergo facile transitions betweenmultiple conformational states under normal conditions [64],and that agonists, neutral antagonists and inverseagonists preferentially bind and stabilize different receptorconformations [61,93,94].

Asmentioned above, there are twomain classes of compoundsknown as aryloxypropanolamines and arylethanolamines,which bind b3-ARs with high affinity.

Perrone & Scilimati


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Although several research groups all over the world have beenworking for achieving the desired highly selective aryloxypropa-nolamines and arylethanolamines b3-AR agonists, the success islimited as no compounds capable either of stimulating orblocking the b3-AR has been so far marketed.The first ligand identified was BRL 37344 [95]. Plenty of

studies were, then, performed in in vitro and in vivo rat mod-els. Unfortunately, BRL 37344 loses ~ 60% of its potency inhumans (Smith-Kline-Beecham’s Phase II) even if the struc-tural homology between human and rat b3-AR is around80 -- 90%. In addition, BRL 37344 does not show b3-ARselectivity in humans [96] and in rodents doses required tocause b3-AR effects also have strong b2-AR effects [97].Other potent b3-AR agonists were identified, such as CL

316243 (SmithKlineBeecham’s compound) [98], AZ 002 [99],BMS 187257 [100], L-755507 and L-750355 [101] andFR-149175 [102].Many companies have identified b3-AR agonists over the past

few decades, which has led to innovative ideas in the attempt todiscover structurally unique b3-AR agonists in this crowdedcompetitive arena;Table 1 lists some exemplificative compoundsselected among a plethora of b3-AR reported agonists.In spite of the very high number of compounds reported as

b3-AR ligands, it is not possible yet to perform at atomic level acorrelation between functional groups, as their steric and elec-tronic features and their distance in the molecule, determiningthe potency and affinity. Some attempts to correlate the chem-ical structure of compounds and their action towards b3-ARhave been accomplished but without any breakthrough [1].

4. Expert opinion

The b3-AR, located at the surface of the adipocytes, has beenshown to mediate, to some extent, events such as lipolysis in

WAT and thermogenesis in BAT. Consequently, several privateand public laboratories have been engaging in developing potentand selective b3-AR agonists for the treatment of diverse humandisease states, such as obesity and type 2 diabetes.

Early b3-AR agonists, which were developed based on therodent models expressing the b3-AR, are represented by BRL37344, CL 316243 and CGP 12177A. BRL 37344 has shownanti-obesity effects, such asmobilization of fat fromWATdepots(lipolysis), increased BAT-mediated thermogenesis and increasedfat oxidation in rodents. In addition to anti-obesity effects, itexhibits potent anti-diabetic effects (increase in insulin secretionand improvement in insulin-mediated glucose uptake) in rodentmodel type 2 diabetes. However, human clinical trials with theseearly agonists have been disappointing due to the lack of selectiv-ity and potency. Subsequent cloning and expression of thehuman and rat b3-ARs indicated a significant difference betweenthe two receptors. This led to the recognition that a clonedhuman receptor assay would offer major advantages over rodentmodels for the identification of second generation of b3-AR ago-nists, such as tethrahydroisquinolines, SB-226552, L-755507and L-770644. They were found as highly potent and selectiveb3-AR agonists by Chinese hamster ovary (CHO) cellsexpressing the cloned human b1-, b2- and b3-ARs.

Despite the difference between the human and rat b3-ARs,further study demonstrated that the treatment of lean volunteerswith CL 316243, developed on rodent models, did inducelipolysis and fat oxidation and increased insulin sensitivity. Thesenew findings clearly suggest that desired metabolic effects couldbe achieved byb3-AR.This encouraged several companies to con-tinue the b3-AR agonist discovery program. Recently, preclinicaland clinical investigations performed by using b3-AR agonistshave been focused on diseases such as urinary bladder dysfunc-tions, gut disorders, anxiety and depression. In particular,in-depth studies were reported for the following compounds:

Substitutionlowers activity

Involved in ionic bondingto receptor binding site

One or two alkyl substituents required.Larger substituents increase selectivity for β-receptors. The larger thesubstituent is the greater the β3-selectivityis. R groups should be large toincrease β3-AR selectivity and have to bear polar and/or ionizable functionalities including ureas, acylamides, sulfonamides and sulfonic,phosphonic and carboxylic groups.The nitrogen can be tertiaryfor β3-selectivity.

Involved in H-bondingto receptor binding site

Aromatic ring involved invan der Waals interactions

Can be modified withother H-bonding groups,or replaced by H, Cl

Involved in H-bondingto receptor binding site,especially to β-receptors

meta

para

HO

HO

XNHR′R″

OH

*

Figure 3. b3-AR ligand structure--activity relationship.*(R)-enantiomer more active than (S)-enantiomer in the arylethanolamine series (X is a direct link between (un)substituted aromatic and ethanolamine moieties);

vice versa in the aryloxypropanolanine series (X = OCH2).



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Table

1.Representativeb3-A

Ragonists,antagonists

andinverseagonists.

Compound

EC50(nM)

Ref.

Humanb1

b2

b3(%

IA)

b3-ARagonists

H N

OH

Cl

OC

O2H

BRL37344

1700

290

21(95)

[103]

H N

OH

Cl

OOC

O2N

a

CO

2Na

(Lederle)CL316243

>10,000

>10,000

18(20)

[104]

*b 1-andb 2-ARantagonist.

z b1-andb 2-ARinhibitors.Itactivatesrecombinanthumanb 3-ARsexpressedin

CHO

cells

withahigherpotency

against

b 3-ARthanagainst

b 1-ARandb 2-ARsbyfactors

of380and‡630times,

respectively.

§b 3-ARagonisticactivitywasassessedbymeasuringrelaxantresponse

inraturinary

bladdermuscle.

{ b1-andb 2-AR,Ki>10,000nM.

#Low

b 1-andb 2-ARbindingaffinity(IC50=13,000and6300nM,respectively).

**Low

b 1-andb 2-ARbindingaffinity(IC50=4800and1800nM,respectively).

zzLow

b 1-andb 2-ARbindingaffinity,

Ki>5000nM.

§§pD2.

{{Ratcolon.

##Low

b 1andb 2

bindingaffinity,

Ki>5000nM.

AR:Adrenoceptor;CHO:Chinese

hamsterovary.

Perrone & Scilimati


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Table



andinverseagonists

(continued).

Compound

EC50(nM)

Ref.

Humanb1

b2

b3(%

IA)

HN

NH

O

O

NH

-t-B

u

OH

CGP12177A

-*-*

158(68)

[105,106]*

H N

OH

HO

Cl

OC

O2H

KUC

7322

14,000

6400

3.8

(88)

[90]

H N

OH

Cl

OC

O2H

FR-149175

-z-z

7100

Strosberg

[107,108]z



CHO

cells

withahigherpotency

against

b 3-ARthanagainst



respectively.


inraturinary

bladdermuscle.


#Low


**Low


zzLow


Ki>5000nM.

§§pD2.

{{Ratcolon.

##Low

b 1andb 2

bindingaffinity,

Ki>5000nM.


hamsterovary.



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Table



andinverseagonists

(continued).

Compound

EC50(nM)

Ref.

Humanb1

b2

b3(%

IA)

H N

OH

Cl

OC

O2H

GS-332

-§-§

16(98)

[109]§

H N

OH

Cl

OOC

O2H

N-5984

--

1.7

(52)

[110]

N

H NO

OH

H2N

CO

2H

CP-331684

18,000

>10,000

400(80)

[104]



CHO

cells

withahigherpotency

against

b 3-ARthanagainst



respectively.


inraturinary

bladdermuscle.


#Low


**Low


zzLow


Ki>5000nM.

§§pD2.

{{Ratcolon.

##Low

b 1andb 2

bindingaffinity,

Ki>5000nM.


hamsterovary.

Perrone & Scilimati


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Table



andinverseagonists

(continued).

Compound

EC50(nM)

Ref.

Humanb1

b2

b3(%

IA)

NH

*HC

l

HO

I

I OC

H3

>1000

>3000

35(60)

[111]

OH N

HO

OH

P

OH

O

SB-226552

-{-{

2511(70)

[105]{



CHO

cells

withahigherpotency

against

b 3-ARthanagainst



respectively.


inraturinary

bladdermuscle.


#Low


**Low


zzLow


Ki>5000nM.

§§pD2.

{{Ratcolon.

##Low

b 1andb 2

bindingaffinity,

Ki>5000nM.


hamsterovary.



Exp

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Table



andinverseagonists

(continued).

Compound

EC50(nM)

Ref.

Humanb1

b2

b3(%

IA)

OH N

HO

OH

N H

S

N HN

H-n

-Hex

yl

OO

O

L-755507

398

10,000

0.4(52)

[112]

H N

OH

N H

S

N

OO

NN

N

ON

L-770664

1900

1800

13(75)

[104]



CHO

cells

withahigherpotency

against

b 3-ARthanagainst



respectively.


inraturinary

bladdermuscle.


#Low


**Low


zzLow


Ki>5000nM.

§§pD2.

{{Ratcolon.

##Low

b 1andb 2

bindingaffinity,

Ki>5000nM.


hamsterovary.

Perrone & Scilimati


Exp

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Table



andinverseagonists

(continued).

Compound

EC50(nM)

Ref.

Humanb1

b2

b3(%

IA)

H N

OH

N H

SO

O

n =

0 o

r 1

n =

0

N

N

S n

n=0

-#-#

2(100)

[113]#

H N

OH

N H

SO

O

N

N

O

-**

-**

14(84)

[114]**



CHO

cells

withahigherpotency

against

b 3-ARthanagainst



respectively.


inraturinary

bladdermuscle.


#Low


**Low


zzLow


Ki>5000nM.

§§pD2.

{{Ratcolon.

##Low

b 1andb 2

bindingaffinity,

Ki>5000nM.


hamsterovary.



Exp

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pin.

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Table



andinverseagonists

(continued).

Compound

EC50(nM)

Ref.

Humanb1

b2

b3(%

IA)

NH

OH

HO

NH

S

O

O

N

CO

NH

2

1200

-(27)

20(112)

[115]

NH

SO

2Me

HO

H N

N

NS

CO

2H

OH

n-B

u

OO

(6)

(4)

9(110)

[115]



CHO

cells

withahigherpotency

against

b 3-ARthanagainst



respectively.


inraturinary

bladdermuscle.


#Low


**Low


zzLow


Ki>5000nM.

§§pD2.

{{Ratcolon.

##Low

b 1andb 2

bindingaffinity,

Ki>5000nM.


hamsterovary.

Perrone & Scilimati


Exp

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pin.

The

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Table



andinverseagonists

(continued).

Compound

EC50(nM)

Ref.

Humanb1

b2

b3(%

IA)

NH

SO

2Me

HO

H N

N

OH

N ON

HO

O

1190

2720

10(119)

[116]

Ar

OH

H N

NN

R1R

2

O

a) A

r =

p-H

OC

6H4O

, R1

= o

ctyl

, R2

= H

b) A

r =

p-O

H, m

-met

hyls

ulph

onyl

amid

ophe

nyl-O

, R1

= 2

, 5-d

ifluo

robe

nzyl

, R2

= H

c) A

r =

p-O

H, m

-met

hyls

ulph

onyl

amid

ophe

nyl,

R1

= 2

, 5-d

ifluo

robe

nzyl

, R2

= H

a)610

Inactive

8(>

100)

[117]

b)423

Inactive

1(100)

c)2640

10

5(100)



CHO

cells

withahigherpotency

against

b 3-ARthanagainst



respectively.


inraturinary

bladdermuscle.


#Low


**Low


zzLow


Ki>5000nM.

§§pD2.

{{Ratcolon.

##Low

b 1andb 2

bindingaffinity,

Ki>5000nM.


hamsterovary.



Exp

ert O

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Table



andinverseagonists

(continued).

Compound

EC50(nM)

Ref.

Humanb1

b2

b3(%

IA)

ON

G

OH

NS

OO

OC

H3

G =

H, p

-OH

, m-N

O2

SP-21,G

=H

-zz

-zz

49.3

(60)

[83]zz

SP-23,G

=m-NO2

-zz

-zz

3.9

(112)

SP-25,G

=p-O

H-zz

-zz

1.79(71)

HN

O

H NH

O

ON

NH

2

O

LY-377604

--

4.3

[118]



CHO

cells

withahigherpotency

against

b 3-ARthanagainst



respectively.


inraturinary

bladdermuscle.


#Low


**Low


zzLow


Ki>5000nM.

§§pD2.

{{Ratcolon.

##Low

b 1andb 2

bindingaffinity,

Ki>5000nM.


hamsterovary.

Perrone & Scilimati


Exp

ert O

pin.

The

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lthca

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Table



andinverseagonists

(continued).

Compound

EC50(nM)

Ref.

Humanb1

b2

b3(%

IA)

H N

N HO

CO

2H

OH

Cl

Rafabegron(AJ-9677)

6.4

(26)

13(26)

0.062(116)

[119]

HO

H N

OP

OH

O O

SB-251023

--

6.25(66)§§

[120]§§



CHO

cells

withahigherpotency

against

b 3-ARthanagainst



respectively.


inraturinary

bladdermuscle.


#Low


**Low


zzLow


Ki>5000nM.

§§pD2.

{{Ratcolon.

##Low

b 1andb 2

bindingaffinity,

Ki>5000nM.


hamsterovary.



Exp

ert O

pin.

The

r. P

aten

ts D

ownl

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d fr

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form

ahea

lthca

re.c

om b

y U

nive

rsity

of

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on 0

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For

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onal

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Table



andinverseagonists

(continued).

Compound

EC50(nM)

Ref.

Humanb1

b2

b3(%

IA)

H N

N H

OH

O

S

N

NH

2

Merck39

--

0.98

[121]

Cl

H NO

CO

2H

OH

Sanofi-Aventis,

Amibegron(SR-58,611A)

31,622

31,622

501

7943

3.16

3.16

[122]

H NN H

OH

Cl

CO

2H

GlaxoSmithKline(GW-427353)

10,000

10,000

6.9

[123]



CHO

cells

withahigherpotency

against

b 3-ARthanagainst



respectively.


inraturinary

bladdermuscle.


#Low


**Low


zzLow


Ki>5000nM.

§§pD2.

{{Ratcolon.

##Low

b 1andb 2

bindingaffinity,

Ki>5000nM.


hamsterovary.

Perrone & Scilimati


Exp

ert O

pin.

The

r. P

aten

ts D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

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Table



andinverseagonists

(continued).

Compound

EC50(nM)

Ref.

Humanb1

b2

b3(%

IA)

H

H N

N

OH

OS

N

NH

2

Astellas,

Mirabegron(YM

178)

>10,000

>10,000

22.4

(80)

[45]



CHO

cells

withahigherpotency

against

b 3-ARthanagainst



respectively.


inraturinary

bladdermuscle.


#Low


**Low


zzLow


Ki>5000nM.

§§pD2.

{{Ratcolon.

##Low

b 1andb 2

bindingaffinity,

Ki>5000nM.


hamsterovary.



Exp

ert O

pin.

The

r. P

aten

ts D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y U

nive

rsity

of

Que

ensl

and

on 0

5/13

/13

For

pers

onal

use

onl

y.

Table



andinverseagonists

(continued).

Compound

EC50(nM)

Ref.

Humanb1

b2

b3(%

IA)

N

H N

N H

S

SN

CF

3

OH

OO

Merck(L-796568)

4770

2405

3.6

[124]

H N

OC

O2H

OH

HO

Kissei/BI,Ritobegron

38,000

1800

10

[125,126]



CHO

cells

withahigherpotency

against

b 3-ARthanagainst



respectively.


inraturinary

bladdermuscle.


#Low


**Low


zzLow


Ki>5000nM.

§§pD2.

{{Ratcolon.

##Low

b 1andb 2

bindingaffinity,

Ki>5000nM.


hamsterovary.

Perrone & Scilimati


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Table



andinverseagonists

(continued).

Compound

IC50(nM)

b3

pA2

Ref.

Humanb1

b2

b3

b3-ARantagonists

OH N

OH

N H

S

OO

SN

H2

O

O

L748328

--

4.6

8.5

[127]

OH N

OH

N H

S

OO

NH

CO

CH

3

L-748,337

--

68.5

[127]

OH N

OH

SR59,230

4 81

0.5

245

4.2

1.7

8.12

[128]



CHO

cells

withahigherpotency

against

b 3-ARthanagainst



respectively.


inraturinary

bladdermuscle.


#Low


**Low


zzLow


Ki>5000nM.

§§pD2.

{{Ratcolon.

##Low

b 1andb 2

bindingaffinity,

Ki>5000nM.


hamsterovary.



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andinverseagonists

(continued).

Structure

b3

EC50(nM)(IA%

)

pA2

Ref.

b3-ARinverseagonists

H N

OH

OC

O2H

SP-1e

181(-64)

7.89{{

[34]{{,##

H N

OH

OC

O2H

136(-73)

8.16{{

[107]



CHO

cells

withahigherpotency

against

b 3-ARthanagainst



respectively.


inraturinary

bladdermuscle.


#Low


**Low


zzLow


Ki>5000nM.

§§pD2.

{{Ratcolon.

##Low

b 1andb 2

bindingaffinity,

Ki>5000nM.


hamsterovary.

Perrone & Scilimati


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. Solabegron (GW-427353, GlaxoSmithKline), a drugwhich acts as a selective agonist of b3-AR, is being devel-oped for the treatment of OAB (NCT00501267, PhaseII) and irritable bowel syndrome (NCT00394186, PhaseII). It has been shown to produce visceral analgesia byreleasing somatostatin from adipocytes (NCT00401479,Phase I). It has completed also Phase II as a compoundfor treatment of anti-obesity and type 2 diabetes; how-ever, in February 2009, the drug was no longer listedon GSK pipeline and the development is presumed tohave been discontinued.

. Amibegron (SR-58611, Sanofi-Aventis) is a selectiveb3-AR agonist that has completed Phase III clinical trialsfor the treatment of anxiety (NCT00252343) and depres-sive (NCT00252356) disorders. On 2008, amibegronclinical trial program was discontinued probably due toabnormality in the hepatic function (Sanofi-Aventis pressrelease, Paris 31 September 2008) [80,122,124].

. Mirabegron (YM 178, Astellas), a b3-AR agonist, hascompleted Phase III for the treatment of OAB(NCT01043666) [80].

. Ritobegron (KUC 7483, Kissei), a b3-AR agonist, hasbeen developed for the treatment of OAB(NCT01004315, completed Phase III clinical trials) [80].Ritobegron failed to reach the primary efficacy endpoint in pivotal trials and hence was discontinuedby Kissei.

. LY-377604 (Ely Lilly & Co.) has completed Phase IIclinical trials as a compound for treating anti-obesityand type 2 diabetes (NCT00993421) [80].

. L-796568 (Merck) has completed Phase I as ananti-obesity/anti-diabetic drug [124].

. N 5984 (Nisshin Kyorin) with a fair selectivity b2-/b3-AR = 20 and b1-/b3-AR = 73 has completed Phase Iclinical trial as an anti-obesity drug and for treatingtype 2 diabetes [124].

. b3-AR inverse agonists, SP-1e and SP-1g, have beenstudied by CHO and rat/human colon tissue. Theymight be useful for the treatment of the late stage ofthe heart failure, in preventing and treating a wastingcondition such as cachexia, and as a tool to study therole of the b3-AR in which it is necessary to suppressits constitutive activity [1].

Many other compounds have been uncovered as b3-ARagonists; some biological studies have been completed, but alot of work is still needed for their complete pharmacologicalcharacterization, taking also into account the bias intrinsicinto the different tissue ligand-directed signaling measured.

In addition, even if plenty of studies have been accomplishedand many patents filed by most of the largest pharmaceuticalcompanies worldwide and university laboratories, the use ofb3-AR agonists to treat human diseases such as obesity,type 2 diabetes, OAB and irritable bowel syndrome, heat fail-ure, gut disorders, wasting condition, anxiety and depressionremains still to be demonstrated because the physio-pathologic role of the b3-AR in the human body tissues inwhich it is functionally expressed is still to be fully understood.

Declaration of interest

The authors are inventors of one patent cited asWO2008015558 [34] in the reference section, and havereceived no payment in preparation of this manuscript.



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in pharmaceutical compositions.

EP23385; 1981

96. Baker JG. The selectivity of

beta-adrenoceptor agonists at

human beta1-, beta2- and

beta3-adrenoceptors. Br J Pharmacol

2010;160:1048-61

97. Mori A, Miwa T, Sakamoto K,

et al. Pharmacological evidence for

the presence of functional beta

3-adrenoceptors in rat retinal blood

vessels. Naunyn Schmiedebergs


98. American Cyanamid Co. Substituted 5-

(2-((2-aryl-2-hydroxyethyl)amino)propyl)-

1,3-benzodioxoles. US5061727; 1991

99. Microbial Chem Res F and Banyu

Pharma Co. Ltd. N-Methylphenylserine

alkyl ester derivatives and uses thereof.

EP218440; 1987

100. Bristol-Myers Squibb Co. Thiazole and

oxazole-based beta 3-adrenergic receptor

agonists. US5321036; 1994

101. Merck & Co., IncSubstituted phenyl

sulfonamides as selective beta3-agonists

for the treatment of diabetes and

obesityEP611003; 1994

102. Yamamoto H, Takakura S,

Yamamoto T, et al. FR149175, a

beta3-adrenoceptor-selective agonist, is a

possible therapeutic agent for

non-insulin-dependent diabetes mellitus.

Jpn J Pharmacol 1997;74:109-12

103. Harada H, Hirokawa Y, Suzuki K, et al.

Novel and potent human and rat

beta3-adrenergic receptor agonists

containing substituted

3-indolylalkylamines. Bioorg Med

Chem Lett 2003;13:1301-5

104. Weyer C, deSouza CJ. Development of

beta3-adrenoceptor agonists as antiobesity

and antidiabetes drugs in

humans: current status and future

prospects. Drug Dev Res 2000;51:80-93







108. Hatakeyama Y, Sakata Y, Takakura S,

et al. Acute and chronic effects

of FR-149175, a beta3-adrenergic

receptor agonist, on energy

expenditure in Zucker fatty rats.

Am J Physiol Regul Integr Comp Physiol

2004;287:R336-41

109. Morita T, Iizuka H, Iwata T, et al.

Function and distribution of

beta3-adrenoceptors in rat, rabbit and

human urinary bladder and external

urethral sphincter. Smooth Muscle Res

2000;36:21-32

110. Yanagisawa T, Sato T, Yamada H, et al.

Selectivity and potency of agonists for

the three subtypes of cloned human

beta-adrenoceptors expressed in Chinese

hamster ovary cells. Tohoku J Exp Med

2000;192:181-93

111. Hieble JP. Recent advances in

identification and characterization

of beta-adrenoceptor agonists and

antagonists. Curr Top Med Chem

2007;7:207-16



113. Mathvink RJ, Tolman JS,

Chitty D, et al. Potent, selective

3-pyridylethanolamine beta3-adrenergic

receptor agonists possessing a thiazole

benzenesulfonamide pharmacophore.


2000;10:1971-3

114. Ok HO, Reigle LB, Candelore MR,

et al. Substituted oxazole

benzenesulfonamides as potent

human beta3-adrenergic receptor

agonists. Bioorg Med Chem Lett

2000;10:1531-4

115. Hu B, Ellingboe J, Han S, et al.

(4-Piperidin-1-yl)phenyl amides: potent

and selective human beta3-agonists.

J Med Chem 2001;44:1456-66

116. Hu B, Ellingboe J, Gunawan I, et al.

2,4-Thiazolidinediones as potent and

selective human beta3-agonists.

Bioorg Med Chem Lett 2001;11:757-60

117. Ashwell MA, Solvibile WR, Han S, et al.

4-Aminopiperidine ureas as potent

selective agonists of the human

beta3-adrenergic receptor. Bioorg Med

Chem Lett 2001;11:3123-7

118. Sawa M, Harada H. Recent

developments in the design of orally

bioavailable beta3-adrenergic receptor

agonists. Curr Med Chem

2006;13:25-37

119. Harada H, Hirokawa Y, Suzuki K, et al.

Discovery of a novel and potent human

and rat beta 3-adrenergic receptor

agonist, [3-[(2R)-[[(2R)-(3-

chlorophenyl)-2-hydroxyethyl]amino]

propyl]-1H-indol-7-yloxy]acetic acid.

Chem Parm Bull 2005;53:184-98

120. Arch JRS, Kaumannl AJ, Molenaarl P,

et al. Studies on a novel selective

beta3-adrenoceptor agonist in human

right atrial appendage and human white

adipocytes. Br J Pharmacol

1999;126:100P

121. Merck & Co., Inc. Hydroxymethyl

pyrrolidines as beta 3-adrenergic receptor

agonists. WO2009124167; 2009



123. Hicks A, McCafferty GP, Riedel E, et al.

GW427353 (Solabegron), a novel,

selective beta3-adrenergic receptor

agonist, evokes bladder relaxation and

increases micturition reflex threshold in

the dog. JPET 2007;323:202-9

124. King FD. Progress in medicinal

chemistry. Volume 41. Oxford AW;

2003. p. 188

125. van Baak MA, Hul GBJ, Toubro S,

et al. Acute effect of L-796568, a novel

beta3-adrenergic receptor agonist, on

energy expenditure in obese men.

Clin Pharmacol Ther 2002;71:272-9

126. Kissei Pharmaceutical. Phenoxyacetic acid

derivatives and medicinal compositions

containing the same. WO2000002846;

2000

127. Kissei Pharmaceutical. Medicine for

prevention or treatment of frequent

urination or urinary incontinence.

WO2005089742; 2005

128. Candelore MR, Deng L, Tota L, et al.

Potent and selective human

beta(3)-adrenergic receptor antagonists.

JPET 1999;290:649-55



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List of the main patents filed by selected

applicants (mainly pharmaceutically industries)

particularly involved in the development of

beta3-adrenoceptor ligands.

American Home Prod. Transcriptional

regulation of the human beta

3-adrenergic receptor gene.

WO20000044901; 2000

American Home Prod. Phenyl-oxo-

tetrahydroquinolin-3-yl beta-3

adrenergic receptor agonists.

US2002068751; 2002

American Home Prod. 2-Substituted

thiazolidinones as beta-3 adrenergic

receptor agonists.

WO2002006281; 2002

American Home Prod. N-(4-sulfonylaryl)

cyclylamine-2-hydroxyethylamines

as beta-3 adrenergic receptor agonists.

WO2002006274; 2002

American Home Prod. Azolidines as

beta-3 adrenergic receptor agonists.

WO2002006258; 2002

American Home Prod. Substituted

2-(S)-hydroxy-3-(piperidin-4-yl-

methylamino)-propyl ethers and

substituted 2-aryl-2-(R)-hydroxy-

1-(piperidin-4-yl-methyl)-ethylamine


WO2002006255; 2002

American Home Prod. Substituted

arylsulfides, arylsulfoxides and

arylsulfones as beta-3 adrenergic

receptor agonists.

WO2002006250; 2002

American Home Prod. Heterocyclic


WO2002006235; 2002

American Home Prod. Cyclic amine

phenyl beta-3 adrenergic receptor

agonists. WO2002006232; 2002

American Cyanamid Co. Treatment

of glaucoma and ocular hypertension

with beta 3-adrenergic agonists.

US5578638; 2002

American Cyanamid Co. Beta

3-adrenergic agents and their use in

pharmaceutical compositions.

US5482971; 1996

American Cyanamid Co. Beta

3-adrenergic agents benzodioxole

dicarboxylates and their use in

pharmaceutical compositions.

US5480908; 1996

American Cyanamid Co.

Aminocycloalkanobenzodioxoles as

beta-3 selective adrenergic agents.

EP608568; 1996

Asahi Kasei Pharma Corp. Indazole

compound. WO2010041568; 2010

Asahi Kasei Pharma Corp. Indazole

compound. WO2010041569; 2010

Astellas Pharma, Inc. Aminoalcohol

derivatives. WO20051109; 2005


derivatives. AU2006202092; 2006

Bayer AG. 2,6-Substituted chroman

derivatives useful as beta-

3 adrenoreceptor agonists.

WO2002085891; 2002

Bayer AG. Di-substituted aminomethyl

chroman derivative beta-3 adrenoreceptor

agonists. WO2002048134; 2002

Beth Israel Hospital. Transgenic animals

deficient in endogenous beta 3-adrenergic

receptor and uses thereof.

WO9742309; 1997

Boehringer Ingelheim Int. Beta-3-agonist

use for treating kidney and bladder

troubles of a patient with spinal cord

damages. WO2007036543; 2007

Bristol-Myers Squibb Co. Thiazole and

oxazole-based beta 3 adrenergic receptor

agonists. US5321036; 1994

Bristol-Myers Squibb Co.

Catecholamine surrogates useful as

beta 3 agonists. EP659737; 1995

Bristol-Myers Squibb Co. Sulfonic,

phosphonic or phosphinic acid beta

3 agonist derivatives.

US5491134; 1996


Benzo 1,3-dioxole derivatives.

US5488064; 1996


Aryloxypropanolamine beta 3

adrenergic agonists. EP714883; 1996

Bristol-Myers Squibb Co. Catecholamine

surrogates useful as beta 3 agonists.

WO9737646; 1997

Bristol-Myers Squibb Co. Catecholamine

surrogates useful as beta 3 agonists.

US5770615 (1998)


Aminoethylphenoxyacetic acid derivatives

and drugs for pain remission and calculi

removal promotion in urinary lithiasis.

WO9905090; 2010

Bristol-Myers Squibb Co. 2-Hydroxy-

3-(4-hydroxy-3-sulfonamidophenyl)-

propylamines useful as beta 3 adrenergic

agonists. US2002026065; 2002

Centre Nat Rech Scient. Method for

producing adipocytes from non-

differentiated fibroblasts and use

of resulting adipocytes.

WO2000037607; 2002

Centre Nat Rech Scient. Nucleotidic

sequences coding for the murine

adrenergic beta 3 receiver and

applications thereof.

WO9212246; 1992

Cedars Sinai Medical Center.

Method for reducing the likelihood

of the occurrence of cardiac arrhythmias.

US2006019954; 2006

Chen Jian. Synthesis and uses of

synephrine derivatives.

US2005250944; 2005

Kadowaki T, Tobe K, Suzuki R.

Compositions and methods for the

amelioration of leptin resistance.

US2004242485; 2004

Dainippon Pharmaceutical Co. New

2-akylamino-1-phenylethanol

derivative. JP8165276; 1996

Dainippon Pharmaceutical Co.

2-(2-(Indol-3-ly)ethylamino)-

1-phenylethanol derivative.

JP6345731; 1994


Indole derivative.

WO9616938; 1996


Benzothiophene derivative.

JP8157470; 1996


3,7-Disubstituted indole

derivatives

and medicinal compositions

containing the same.

WO2000044721; 2002


Heteroarylsulfonanilide derivative

and medicinal composition


WO2004089936; 2004


Indole compound and

pharmaceutical composition


WO2006078006; 2006


Method for synthesizing indoles

and synthetic intermediate.

JP2006169113; 2006

Perrone & Scilimati


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Sulfonyloxyindole derivative

and medicinal composition containing

the same. JP2006111553; 2006


Novel useful therapeutic agent for

lower urinary tract symptom.

WO2010053068; 2010

Eli Lilly & Co. Selective beta

3 adrenergic agonists.

WO9809625; 1998



WO9929672; 1999



EP921120; 1999

Eli Lilly & Co. Crystalline salts of

2-(4-{2-[2-hydroxy-3-(2-thiophen-2-yl-

phenoxy)-propylamino]-2-methyl-

propyl}-phenoxy)-nicotinonitrile.

WO2002094820; 2002

Eli Lilly & Co. 3-Substituted

oxindole beta 3 agonists.

WO2002038543; 2002



WO2002038544; 2002

Eli Lilly & Co. Beta 3 adrenergic

agonists. WO20020124; 2002



WO2003044016; 2003


agonists. WO2003016307; 2003


agonists. WO2003044017; 2003



WO2003016276; 2003

Fancl Corp. Oligosaccharide-esterified

substance effective for obesity and

diabetes. JP200616018; 2006

Fancl Corp. Lysophosphatidyl choline

effective for obesity, diabetes, etc.

JP200616018; 2006

Fujisawa Pharmaceutical Co.

New pharmaceutical use of beta

3-adrenalin agonist.

JP6293664; 1994

Fujisawa Pharmaceutical Co. New

pharmaceutical use of beta 3-adrenalin

agonist. JP7228543; 1995


Aminoalcohol derivatives and their

use as beta 3 adrenergic agonists.

WO2000012462; 2000


Aminoalcohol derivatives.

WO2002094770; 2002


Aminoalcohol derivatives and their

use as beta 3 adrenergic agonists.

WO2003076397; 2003


Aminoalcohol derivatives and

their use as beta 3 adrenergic

agonists. WO2004045610; 2004



US2004106653; 2004



WO2004002939; 2004

Fujisawa Pharmaceutical Co.,


derivatives. WO2005061433; 2005


Astellas Pharma Inc. Aminoalcohol

derivatives. US2005137236; 2005

Genaissance Pharmaceuticals.

Haplotypes of the adrb3 gene.

WO2002008425; 2002

Glaxo Group Ltd. Phenethanolamine

derivatives and their use as atypical

beta-adrenoceptor agonists.

WO9533724; 1995

Glaxo Group Ltd. Arylethanolamine

derivatives and their use as agonists

of atypical beta-adrenoceptors.

WO9721666; 1997

Glaxo Group Ltd. Naphthalenesulphonic

or carboxylic acids and their use as

atypical beta-adrenoceptor agonists.

WO9843953; 1998

Glaxo Wellcome, Inc. Arylethanolamine

derivatives and their use as agonists of

atypical beta-adrenoceptors.

US6048872; 1998

Glaxo Wellcome, Inc. Therapeutic

biaryl derivatives. WO9965877; 1999

Glaxo Group Ltd. Beta-3 adrenoceptor

agonists. WO0142217; 2001

Glaxo Group Ltd. Chemical compounds.

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Glaxo Group Ltd. Method for producing

arylethanoldiamine useful as agonist of

beta-adrenoceptor. JP2009137946; 2009

Glenmark Pharmaceuticals Ltd. Novel

benzopyran compounds and process for

their preparation and use.

WO2003014113; 2003

Imperial Chemical Industries Plc.;

Zeneca Ltd. 2-Hydroxy-

2-phenylethylamine derivatives as

beta-3-adrenoceptor agonists.

EP516350; 1992

Kaneka Corp. Human beta

3-adrenalin receptor agonist agent.

WO2006213657; 2006

Kaken Pharmaceut Co. Ltd.

Phenylethanolamine derivative.

JP7112958; 2000

Kissei Pharmaceutical. Preventive/

remedy for frequent urination and

urinary incontinence.

WO9807445; 1998

Kissei Pharmaceutical.

2-Methylpropionic acid derivatives

and medicinal compositions


WO9952856; 1999


Phenylaminoalkylcarboxylic acid

derivatives and medicinal


WO9931045; 1999


Aminoethylphenoxyacetic acid

derivatives and drugs for pain

remission and calculi removal

promotion in urinary lithiasis.

WO9905090; 1999

Kissei Pharmaceutical. Crystal

polymorphism of

aminoethylphenoxyacetic acid

derivative dihydrate.

JP2000212137; 2000


polymorphism of


derivative dihydrate.

JP2000212138; 2000


polymorphism of




polymorphism of


derivative. WO2000043350; 2000

Kissei Pharmaceutical. Phenoxyacetic

acid derivatives and medicinal


WO2000002846; 2000



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Kissei Pharmaceutical. Amino alcohol

derivative, medicinal composition

containing the same, and uses of these.

WO2004108674; 2004


derivatives, pharmaceutical compositions

containing the same, and use of both.

WO2004106290; 2004



containing the same, and uses of these.

WO2004106283; 2004



containing the same, and use of these.

WO2005040093; 2005

Kissei Pharmaceutical. Method for

producing aminoalcohol derivative having

biphenyl group. WO2006123672; 2006

Kissei Pharmaceutical. Pharmaceutical

composition for prevention or treatment

of neurogenic pain.

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Kissei Pharmaceutical. Preventive or

therapeutic agent for disease caused by

decrease in lacrimal fluid.

WO2007026630; 2007

L’oreal. Use of alverine or one of its

salts. WO2002080877; 2002

Malak JCEG. Chemical compounds

derived from octopamine and their uses

as beta 3-adrenergic agonists.

WO2002081424; 2002

Medicinova, Inc. Method of treatment

or prophylaxis of depression.

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Merck & Co., Inc. Substituted

phenyl sulfonamides as selective beta

3 agonists for the treatment of

diabetes and obesity.

EP611003; 1994


sulfonamides as selective beta

3 agonists for the treatment of diabetes

and obesity. US5561142; 1996


sulfonamides as selective beta 3 agonists

for the treatment of diabetes and obesity.

US5541197; 1996

Merck & Co., Inc. Oxadiazole

benzenesulfonamides as selective beta

3 agonists for the treatment of diabetes

and obesity. WO9746556; 1997

Merck & Co., Inc. Selective B3 agonists


GB2305665; 1997

Merck & Co., Inc. Thiazole

benzenesulfonamides as beta 3 agonists


WO9832753; 1998

Merck & Co., Inc. Combination therapy


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sulfonamides as selective beta -3 agonists


US5705515; 1998

Merck & Co., Inc. Fused piperidine

substituted arylsulfonamides as beta

3-agonists. WO9944609; 1999


for the treatment of urinary frequency,

urinary urgency and urinary

incontinence. WO2007044296; 2007


for the treatment-of lower urinary tract

symptoms. WO2008121268; 2008

Merck & Co. Inc. Hydroxymethyl

pyrrolidines as beta 3 adrenergic

receptor agonists.

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pyrrolidines as beta 3 adrenergic receptor

agonists. WO2009124166; 2009


pyrrolidines as beta 3 adrenergic

receptor agonists.

WO2009124167; 2009

Metabolic Pharm Ltd. Product and

method for control of obesity.

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Pfeizer, Inc. beta3-adrenoceptor agonists

and antagonists for the treatment of

intestinal motility disorders, depression,

prostate disease and dyslipidemia.

CA2158910; 1996

Pfeizer, Inc. Heterocyclic beta-

adrenergic agonists. EP8021060; 1997

Pfeizer, Inc. Heterocyclic beta-

adrenergic agonists. US5843972; 1998

Pfeizer, Inc. Sulfamide derivatives useful

as beta3 agonists and pharmaceutical uses

thereof. EP1236723; 2002

Pfeizer Products, Inc. Alpha-aryl

ethanolamines and their use as beta-

3 adrenergic receptor agonists.

WO2002032897; 2002

Pfeizer, Inc. Combinations of beta

3 agonists and growth hormone

secretagogues. US6657063; 2003

Pfeizer Products, Inc. Crystal forms of

(R)-2-(2-(4-oxazol-4-yl-phenoxy)-

ethylamino)-1-pyridin-3-yl-ethanol.

WO2003072573; 2003

Pfeizer Products, Inc. Crystal forms of

(R)-2-(2-(4-oxazol-4-yl-phenoxy)-

ethylamino)-1-pyridin-3-yl-ethanol.

WO2003072573; 2003

Pfeizer Products, Inc. Salt of a pyridyl

ethanolamine derivative and its use

as a beta-3-adrenergic receptor agonist.

WO2003072571; 2003

Pfeizer, Inc. Beta 3 adrenergic receptor

agonist crystal forms, processes for the

production thereof, and uses thereof.

US2003166686; 2003

Ricom Corp. Human beta3-adrenergic

receptor ligand, and food or

pharmaceutical product containing the

same. WO2009151094; 2009

Sanofi SA; Midy SPA. Phenylethanol

aminotetralines, process for their

preparation and pharmaceutical

compositions containing them.

EP0211721; 1987

Sanofi SA; Midy SPA. Process

for the preparation of

phenylethanolaminotetralines.

EP0303545; 1989

Sanofi SA; Midy SPA.

Phenylethanolaminomethyltetralins,

procedure for their preparation and

pharmaceutical compositions

containing same. EP0436435; 1991

Sanofi ELF; Midy SPA.

Phenylethanolamino- and

phenylethanolaminomethyltetralines,

process for their preparation,

intermediates of this process and

pharmaceutical compositions

containing them. EP0500443; 1992

Sanofi ELF; Midy SPA. (7S)-7-(2

(3-chlorophenyl)-2-hydroxyethylamino-

5,6,7,8-tetrahydro-naphthalen-2-yloxy

acetic acid, their pharmaceutically

acceptable salts with a

beta-3-adrenergic agonist activity

and pharmaceutical compositions

containing them. EP0627407; 1994

Sanofi SA; Midy SPA. (7S)-7-(1R)-

2-(3-chlorophenyl)-2-hydroxyethylamino-

5,6,7,8-tetrahydronaphtalen-2-yloxy

acetic acid, their pharmaceutically

acceptable salts with a beta-3-adrenergic

agonist activity and pharmaceutical


EP0626367; 1994

Perrone & Scilimati


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Sanofi SA. Use of agonists of adrenergic

beta-3 receptors for preparing wound-

healing medicines. WO9831357; 1998

Sanofi SA. Use of central cannabinoid

receptor antagonists for regulating

appetence. WO9832441; 1998

Sanofi SA. Phenoxypropanolamines

having beta 3-adrenergic antagonist

activity. WO9803485; 1998. This patent reports the discovery of

the first b3-adrenoceptor antagonist.

Sanofi Synthelabo.

Phenoxylpropanolamines, method for the

production thereof and pharmaceutical


WO9965895; 1999

Sanofi Synthelabo. Heteroaryloxy

propanolamines, preparation method


containing same. WO0117989; 2001

Sanofi Synthelabo.

Phenoxypropanolamines, method for

producing them and pharmaceutical


WO2001043744; 2001

Sanofi Synthelabo.

Phenoxypropanolamines, preparation

and therapeutic use thereof.

WO2001044227; 2001

Sanofi Synthelabo.

Propanolaminotetralines, preparation

thereof and compositions containing

same. WO2001094307; 2001

Sanofi Synthelabo. Cyclohexyl(alkyl)-

propanolamines, preparation method


containing same.

WO2002044139; 2002

Sanofi Synthelabo.

Propanolaminomethyltetralines,

their preparation and pharmaceutical

composition comprising same.

FR2833010; 2003

Sanofi Synthelabo.

Propanolaminomethyltetralines,

their preparation and pharmaceutical

composition comprising same.

WO2003048117; 2003

Sanofi Synthelabo.

Phenylcyclohexylpropanolamine

derivatives, preparation and

therapeutic application thereof.

WO2003099772; 2003

Sanofi Synthelabo. Oxophenyl-

cyclohexyl-propanolamine

derivatives, production and use

thereof in therapeutics.

WO2003099819; 2003

Sanofi Aventis. Novel therapeutic

uses of beta-3 adrenergic receptor

agonist derivatives in particular to

modulate apoptosis.

WO2009019607; 2009

Sanofi Aventis. Beta adrenergic

receptor ligand derivatives for

modulating apoptosis.

EP2011490; 2010

Smithkline Beecham PLC.

Arylethanolamine derivatives and their

use as beta-3-adrenoceptor agonists.

WO9310074; 1993

Smithkline Beecham PLC.

Arylethanolamine derivatives and

their use in the treatment of

obesity and hyperglycaemia.

WO9424090; 1994

Smithkline Beecham PLC. Aryloxy

andarycthio propanolamine derivatives

useful as beta3-adrenoreceptor agonists

and antagons of the beta1- and

beta2-adrenoreceptors and

pharmaceutical composition thereof.

WO9604234; 1996

Smithkline Beecham PLC. Aryloxy

and arylthiopropanolamine derivatives

useful as beta 3-adrenoreceptor

agonists and antagonists of the

beta 1- and beta 2-adrenoreceptors

and pharmaceutical composition thereof.

WO9604233; 1996

Sumitomo Pharma. Cyclic amine and

medicinal composition containing the

same. WO2003106423; 2003

Sumitomo Pharma. Indole, indazole,

and benzazole derivative.

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Sawai Seiyaku Kk. Phenoxyacetic acid


Tokyo Tanabe Co. Ltd.

Tetrahydrobenzothiophene derivative.

JP10152488; 1998

Toyo Shinyaku Co. Ltd. Enhancer of

expression of beta 3-adrenergic receptor.

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Univ Wayne State. Beta 3-adrenergic

receptor protein and DNA encoding

same. WO9402590; 1994

Univ Maryland. Genetic markers which

identify individuals who improve their

diabetes status with exercise.

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Univ Johns Hopkins Med. Susceptibility

gene for obesity and type ii diabetes

mellitus. JP2006169113; 2006

Vetigen. Canine beta 2- and beta

3-adrenergic receptors and use thereof.

WO9735973; 1997

Vetigen. Nucleotide sequences coding

for the bovine beta 3-adrenergic

receptor, and applications thereof.

WO9424162; 1996

Virbac SA. Aryloxypropanolamine

derivatives, method of preparation

and applications thereof.

WO9820005; 1998

4SC AG. Aryloxypropanolamines,

methods of preparation thereof and use

of aryloxypropanolamines as

medicaments. WO2008090140; 2008

Univ. degli Studi di Bari. Beta-3

receptor ligands and their use in

therapy. WO2008015558; 2008

Univ. Reading. Beta adrenergic receptor

pharmacophore. WO2007045893; 2007

Univ North Carolina. Methods and

materials for determining pain sensitivity

and predicting and treating related

disorders. WO2007001324; 2007

Yamanouchi Pharmaceut Co. Ltd.

New guanidine derivative or salt

thereof. JP10158233; 1998

AffiliationMaria Grazia Perrone & Antonio Scilimati†

†Author for correspondence

University of Bari,

Dipartimento Farmaco-Chimico,

Via E. Orabona, 4,

70125 Bari, Italy

Tel: +39 0805442762; Fax: +39 0805442724;

E-mail: [email protected]



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β 3 -Adrenoceptor ligand development history through patent review

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