Muscarinic antagonist-β-adrenergic agonist dual pharmacology molecules as bronchodilators: a patent...

Review

10.1517/13543770802630331 © 2009 Informa UK Ltd ISSN 1354-3776 1All rights reserved: reproduction in whole or in part not permitted

Muscarinic antagonist- b -adrenergic agonist dual pharmacology molecules as bronchodilators: a patent review Nicholas C Ray † & Lilian Alcaraz † Argenta Discovery Ltd, 8-9 Spire Green Centre, Flex Meadow, Harlow, Essex CM19 5TR, UK

Background : The proven efficacy of several anti-cholinergics and β 2 -agonists and their combinations in both chronic obstructive pulmonary disease (COPD) and asthma strongly validates this therapeutic approach. As a consequence and although technically challenging, over the past 4 years there has been a growing interest in the generation of dual pharmacology Muscarinic-receptor antagonists- β 2 -adrenergic receptor agonists (MABAs) for the treatment of COPD. Objective/methods : This article surveys and reviews the research activity in the MABA area to the end of August 2008. Results/conclusion : Although the activity in this field seems to still be limited to a few companies, significant progress in the discovery of a MABA has been achieved with the progression of at least one candidate (GSK-961081) to the clinic.

Keywords: chronic obstructive pulmonary disease , Muscarinic receptors , β 2 -adrenergic receptor , β 2 -adrenoceptors

Expert Opin. Ther. Patents (2009) 19 (1):1-12

1. Introduction

First-line treatment for a variety of pulmonary disorders including chronic obstructive pulmonary disease (COPD) and asthma is through the use of bronchodilators [1-4] . Muscarinic-receptor antagonists (anti-cholinergics) are bronchodilators that exert their efficacy by reducing vagal cholinergic tone, the main reversible component of airway constriction in COPD. The efficacy of anti-cholinergics is thought to be predominately mediated by blockade of the M 3 receptor; however, most anti-cholinergics show relatively poor selectivity against the other muscarinic receptors, especially M 1 , and blockade of some of these may conceivably contribute to their beneficial effects. β 2 -Agonists provide similar levels of bronchodilatation to that observed with anti-cholinergics by activating the β 2 -adrenoceptor. This elicits increases in cAMP levels that oppose (functionally antagonize) the bronchoconstrictor responses generated by a range of mediators including acetylcholine.

In addition to improving lung function, these agents reduce hyperinflation, which leads to less dyspnea (breathlessness) and possibly increased exercise tolerance and they also reduce exacerbations. Several clinical studies [5-9] have clearly demonstrated that combined administration of an anti-cholinergic and a β 2 -receptor agonist is more efficacious than either of the individual components alone (e.g., tiotropium and formoterol). These data suggest that a single molecule possessing activities at both muscarinic and β 2 -receptors (MABAs) has the potential to provide extra benefits to COPD patients in terms of efficacy and side-effect profile over either single agent. Moreover, a molecule possessing dual activity may

1. Introduction

2. Patent review

3. Conclusion

4. Expert opinion

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Muscarinic antagonist-b-adrenergic agonist dual pharmacology molecules as bronchodilators: a patent review

2 Expert Opin. Ther. Patents (2009) 19(1)

also offer benefits in terms of ease-of-use and patient compliance over sequential administration of each therapy. Furthermore, a single agent may be highly beneficial from the perspective of formulation compared to two separate com-pounds requiring formulation for delivery in the same device and may also offer a unique opportunity, if united with another anti-inflammatory agent (e.g., an inhaled corticosteroid, ICS), for the simplification of the somewhat more technically challenging triple combination approach to therapy [10,11] . The pathway to regulatory approval for a single agent would also be significantly simplified compared to a combination of two or more agents, as gaining regulatory approval for a dual combination is likely to require taking each new chemical entity (NCE) to new drug application (NDA) stage individually and in combination, adding greatly to difficulty and cost.

The company furthest advanced in the field is Theravance; recently they have released the first data from a Phase II trial [12] for compound GSK961081 (possibly compound 2 , Figure 1 , vide infra ). In this study, GSK961081 dosed at both 400 and 1,200 µg/day showed bronchodilatation at day 14 that was at least equivalent to salmeterol 50 µg b.i.d. + tiotropium (Tio) 18 µg u.i.d. as measured by changes in Forced expiratory volume in 1 second (FEV 1 ). Both the time to peak effect and maximum bronchodilatation of GSK961081 were numerically better than salmeterol + Tio, although the study was not powered to compare the results to salmeterol + Tio control.

2. Patent review

So far all the applications published in the MABA area have been based around the conceptual framework of bifunctional β 2 -agonist/M 3 -antagonist first demonstrated by Theravance and generally claiming ‘high lung selectivity’. In this approach M 3 / β 2 dual activity compounds are designed by the linkage of known M 3 and β 2 chemical features using a suitable linker. The resulting molecules contain the two basic centers present in the two original components and so far no one has succeeded in merging them into a single common pharmacophoric anchor point [13] .

2.1 Theravance/GSK Theravance were the first to enter the MABA patenting field, their first application appearing in 2004. Since that time 12 patent cooperation treaty (PCT) applications have been published, 6 of which have led to granted US patents. A further 12 Continuations and Divisions within these patent families have also been published. In March 2005, GlaxoSmithKline (GSK) exercised its option to license Theravance’s MABA program, and some of the more recent filings appear under the GSK name with GSK inventors.

The Theravance/GSK patent estate is based around three distinct classes of anti-muscarinic scaffolds that can be termed i) biphenylcarbamates; ii) Darifenacin scaffolds and; iii) tropane scaffolds.

2.1.1 Biphenylcarbamates The biphenylcarbamate-based MABAs were the first to be disclosed, with three PCT applications appearing in September 2004. The biphenylcarbamate motif in anti-muscarinics was not new; it had previously been disclosed by Yamanouchi (now Astellas) in YM-46303 ( Figure 1 , 1 ) for the treatment of urinary incontinence [14] . In the first application [15] , the biphenylcarbamate (or urea) is attached to a 4-piperidyl group and then through a linking group to the β -agonist moiety, which is preferably of the quinolinone, formamide or catechol type. Claimed values for the linking group are broad, but all groups join the two pharmacophoric units via their respective basic nitrogen groups. A total of 186 examples are presented; data from a range of in vitro and in vivo assays for Example 3 (compound 2 , Figure 1 ) are given. Compound 2 showed β 2 and M 3 membrane binding Kis of < 10 nM and β 1 Ki/ β 2 Ki > 8, an EC 50 < 10 nM in a cAMP assay in Chinese hamster ovary (CHO) cells and β 1 EC 50 / β 2 EC 50 > 10. In a FLIPR ™ calcium release assay in CHO cells 2 had a Ki < 10 nM against human M 1 and M 3 , and chimpanzee M 5 receptors, and a Ki < 10 nM in a GTP γ S assay (CHO cells) against M 2 . Compound 2 was also examined in pharmacodynamic models of bronchoconstriction, the chemically induced bronchoconstriction model in guinea pigs. Dosing route was by inhalation in whole-body chambers of nebulized aerosol solutions over 10 min. Animal pretreatment with propanolol (a β -antagonist) followed by the broncho-constrictor acetylcholine isolates the anti-muscarinic effect of subsequent treatment with a MABA, whereas contraction with histamine assesses the β 2 component. Compound 2 showed an ID 50 < 100 µg/ml against both spasmogens when administered 1.5 h post-dose, an effect that lasted at least 24 h post-dose.

A symptom of systemic M 3 antagonism is decreased salivary production, the so-called Dry Mouth, and hence the determination of a compound’s ability to inhibit pilocarpine (a muscarinic agonist) induced salivation can be used to provide an estimate of therapeutic index (TI). Compound 2 was stated to have a TI (anti-sialagogue ID 50 /bronchoprotective ID 50 ) > 5. Additionally, an application for a crystalline form of the napadisylate (naphthalene-1,5-bissulfonate) of 2 has appeared [16] . A further example from [15] (Example 25, 3 ) has been the subject of two crystalline form applications: as the edisylate (ethane-1,2-disulfonate) [17] and the succinate [18] . That the inventors on this latter patent are GSK rather than Theravance scientists, combined with the information that a succinate salt was tested in the Theravance Phase I study [19] , points to this compound possibly being the Theravance clinical candidate GSK961081.

Two other PCT applications [20,21] that claim priority from the same cases as does [15] earlier have appeared, the first with a broader linker group claim, and the second describing a library of biphenyl compounds. The same 186 examples appear in all three cases.

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Expert Opin. Ther. Patents (2009) 19(1) 3

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Biphenyl compounds where the β 2 moiety can be a benzothiazolone (or other phenyl-fused heterobicycle), with or without a benzylic hydroxyl group, are claimed in [22] . The linking group definition seems similar to that claimed in [15] earlier. A total of 584 representative examples are given, all containing the hydroxybenzothiazolone or des-hydroxy benzothiazolone motif, and only 4 compounds are exemplified by synthesis. All examples had M 3 binding Kis of < 10 nM and β 2 EC 50 values of < 30 nM, with a > 10-fold selectivity over β 1 . No in vivo data were reported. Additionally, some of the compounds showed activity at the D 2 receptor, with 4 showing > 75% inhibition at 100 nM. That 4 showed D 2 activity may not be completely unexpected, as the AstraZeneca compound sibenadet ( 5 ) is a dual β 2 -agonist/D 2 agonist. Also, on the basis of the results previously published [23] for compounds containing the des-hydroxy benzothiazolone motif, it is highly likely that analogues of type 4 are only partial agonists at the β 2 -receptor.

The biphenyl area was broadened in [24] (see bibliography for a detailed review of this application) wherein i) the distal phenyl group of the biphenyl group may be replaced with other heterocycles (specifically identified are 3-thienyl, 2-thiazolyl and 3-pyridyl) and; ii) the piperidine ring of the antimuscarinic moiety is broadened to include acyclic groups, as well as permitting ring closure onto the nitrogen of the urea. The linking group definitions were similar to those in earlier cases. Five compounds including 6 are exemplified by synthesis; potencies of < 300 nM against both receptors are claimed but no other specific data are reported. A further application [25] published on the same day combined the broadened biaryl motif, but coupled to the azacyclic rings familiar from earlier applications, exemplified by compounds such as 7 together with a further 13 examples. Another 14 compounds are exemplified by synthesis. Binding and whole cell func-tional data are presented and fall within a similar range to compounds presented in earlier applications.

A selection application [26] published at the end of 2007 claimed a subset of compounds originally described in [15] , containing the formoterol tail and a di-substituted anilide in the linking group. Compound 8 , in various salt forms, is the sole compound exemplified. In this application, 8 is claimed as having a nonselective muscarinic profile with a binding Ki of < 10 nM, a β 2 EC 50 < 10 nM, a β 1 EC 50 ∼ 30 nM and a β 3 EC 50 > 700 nM. The compound was evaluated in the same multiple challenge Einthoven inhalation guinea pig model as described for 2 and gave an ID 50 of 50 µg/ml for both histamine- and methacholine-induced bronchoconstriction, as well as significant bronchoprotection at 72 h when dosed at 100 µg/ml. In this application, 8 is compared against the des-methyl analogue, which is an example in [15] , with a comment that the des-methyl compound displays no significant bronchoprotection at 24 h in the plethysmograph guinea pig assay at a range of doses from 3 to 300 µg/ml. However, the reviewers can find no comment that 8 itself is effective in this assay. The crystallization of the free base is described

and this particular form was deemed of sufficient importance to warrant a separate filing [27] .

2.1.2 Darifenacin scaffolds Darifenacin ( 9 , Figure 2 ) is an orally administered muscarinic antagonist originally developed by Pfizer and licensed to several third parties for the treatment of urinary incontinence. Incorporation of this anti-muscarinic moiety into a MABA has led to compounds as exemplified in a single application [28] . A total of 300 compounds, all containing the diphenylcarboxamide moiety as per darifenacin, are identified as representative compounds with enabling methods supplied, divided between 150 linking groups coupling the anti-muscarinic group to either the formoterol or quinolinone moieties. No compound seems particularly preferred. Some representative data are provided for 10 : M 3 Ki < 50 nM, β 2 EC 50 < 10 nM and β 2 / β 1 selectivity of > 10. No in vivo data are provided.

2.1.3 Tropane scaffolds MABA compounds based on the tropane scaffold as present in the known anti-muscarinic tiotropium 11 are disclosed in a single application [29] . As in [28] earlier, 150 linkers are coupled to either of the formoterol and quinolinone β 2 -agonist headgroups, and the tiotropium headgroup, with enabling methods. Representative data (in a similar range as per 10 earlier) are presented and no compounds seem particularly preferred. A representative structure is shown ( 12 , Figure 2 ), which interestingly contains a quaternary center at the muscarinic end, rather than the more usual tertiary amine.

2.2 Argenta/Astrazeneca In January 2007 Argenta Discovery and AstraZeneca announced a collaboration to discover both long-acting anti-muscarinics (LAMAs) and MABAs [30] . Argenta Discovery has disclosed a series of oxazole-based muscarinic antagonists [31,32] wherein the two pharmacologies are linked by an alkylene, alkenylene or alkynylene chain. A range of β 2 -head groups are claimed; the examples contain two, the benzthiazolone and quinolinone. A total of 10 examples are included (all of which contain an alkylene chain) and compound 13 ( Figure 3 ) is more extensively profiled: M 3 binding Ki of 0.85 nM, β 2 -binding Ki of 99 nM, β 2 cAMP EC 50 (CHO cells, Alphascreen) of 37 nM and M 3 functional assay (also in CHO cells) of 209 nM. In an electrical field stimulated (EFS) isolated guinea pig trachea experiment the same compound showed an EC 50 of 153 nM, but no onset or duration data were provided, nor were data showing that there were contributions from both pharmacologies presented. In a subsequent application [33] , oxazoles are expanded to a wider range of 5-membered heterocyclic rings but no MABA compounds are specifically exemplified. A similar range of heterocycles are claimed in [34] but the linking group is expanded to allow for the presence of rings and heteroatoms. A total of 21 MABA examples, all containing the oxazole

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heterocyclic group, are exemplified by synthesis and some primary data are presented. Compound 14 ( Figure 2 ) had an M 3 pIC 50 of 9.1 and β 2 pEC 50 of 7.7 (intrinsic activity 0.9). The exemplified compounds contain either the known benzothiazolone or quinolinone β 2 moieties.

A further series of MABAs based on a norbornane scaffold has also appeared from Argenta [35,36] , containing three examples. All examples contain the quinolinone β 2 -headgroup; the norbornane unit is substituted with either an ester 15 or carbamate 16 . In both sets of applications, the two pharma-cophoric elements are joined by an alkylene chain. A recent application [37] broadened the scope of the linking group to include rings and heteroatoms. A total of 13 compounds are exemplified by synthesis: Example 2 ( 17 , Figure 2 ) showed M 3 pIC 50 of 9.2 and β 2 pEC 50 of 8.1 (intrinsic activity 1.0).

2.3 Boehringer–Ingelheim Boehringer–Ingelheim make extensive use of the benzo [1,4] oxazin-3-one scaffold in their β 2 agonist applications and this theme is carried over into this MABA application [38] . That Boehringer–Ingelheim use the tropane scaffold as the anti-muscarinic moiety is not surprising, as this organization developed Tiotropium. No specific biological data are presented; two structures that might be considered as MABAs are presented, including 18 ( Figure 3 ).

2.4 Novartis A published single application from Novartis interestingly claims compounds that are β 2 agonists and that may also possess M 3 antagonist activity and/or PDE 4 activity [39] . Five examples are given but no data indicating which may be regarded as MABAs are presented. However, Example 5 ( 19 , Figure 4 ) is likely to be a MABA. The anti-muscarinic moiety is recognizable from previous art, containing as it does either the biphenylcarbamate or diarylglycolate units joint to a cyclic amine. It is interesting to note that compounds from this invention are claimed to have rapid onset of action and prolonged stimulation (up to 24 h) at the β 2 -receptor when tested in a guinea pig trachea strip in vitro assay. The reviewers also note that compound 19 seems similar to compounds in Theravance’s WO2005051946 application [22] .

2.5 Pfi zer Two applications have appeared from Pfizer, describing different scaffolds. The first [40] uses the anti-muscarinic moiety as known in Pfizer/Nycomed’s tolterodine ( 20 , Figure 4 ; an orally active anti-muscarinic for treatment of urinary incontinence), attached to a range of known β 2 moieties, but with an emphasis on the methanesulfonamide unit familiar from Pfizer’s own β 2 agonist patent estate [41] , and the quinolinone motif. Interestingly, and uniquely among published MABA applications, the two groups are not linked by the two basic amine moieties of each pharmacophore, but from one of the tolterodine aryl group to the β 2 amine. Also contrary to some of the broad claims for the linker group in many other

applications, the linking moiety is limited to alkylene, alkylene ethers (and thioethers) and arylalkylene ether linkers, most of the examples bearing this latter functionality. A total of 20 examples are described; β 2 whole cell functional data for all compounds are presented together with whole cell M 3 binding data, both in CHO cells. Compound 21 is the most potent at β 2 (EC 50 0.028 nM, M 3 Ki 0.39 nM), whereas 22 is the most potent at M 3 ( β 2 EC 50 0.25 nM, M 3 Ki 0.060 nM), although this latter compound is not included in the most preferred compound set within the application. One compound ( 23 ) is prepared on the gram scale as a succinate salt, indicating perhaps heightened interest for this compound (note the missing phenolic hydroxyl group in the structure in the patent).

Pfizer’s second application [42] covers structures related to those described by Theravance [15] , using the same biphenyl carbamate anti-muscarinic motif but attached to the arylsulfonamide β 2 moiety. Additionally, the biphenyl group has a 3′-halo-4′-hydroxy substitution pattern. Six examples are presented: three parents, each with their respective napadisylate (naphthalene-1,5-disulfonate) salt, all containing a -(CH 2 ) 9 - linking group (although arylalkylene groups are also claimed). The most potent example 24 showed a β 2 EC 50 of 0.133 nM and a M 3 Ki of 0.725 nM.

3. Conclusion

Since the first Theravance applications appeared in 2004 several other companies have entered the area, with the largest number of applications after Theravance/GSK belonging to Argenta/AstraZeneca. One might reasonably expect further applications from the companies mentioned earlier, and the promising clinical data from Theravance may encourage other companies with respiratory franchises to enter the fray.

4. Expert opinion

In the light of the positive outcome of many combination studies in which sequential administration of a muscarinic antagonist and a β 2 -receptor agonist have displayed clinical advantages in COPD patients, the interest in MABA compound is evermore increasing. The recent disclosure of the Theravance Phase II data on GSK961081 has provided proof of concept of this approach in the clinic. So far, MABAs have been exclusively obtained by combining known muscarinic and β 2 -adrenergic pharmacophores in a single molecule that together with the linking group has led to relatively large molecules. As delivery will be by inhalation the usual concerns of poor oral bioavailability and rapid systemic clearance that might be anticipated in such molecules may actually be beneficial, but it will probably add complexity to the identification of suitable crystalline forms. However, the presence of a few (crystalline) salt selection patents demonstrate this is an achievable goal. The presence of two pharmacophores raises the possibility of inheriting

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the off-target effects of both, which will need to be addressed in any lead optimization campaign. This can already be deduced from some of the patent applications in which nonselectivity against the other muscarinic receptors (M 1 , M 2 , M 4 and M 5 ) as well as activity at related other adrenergic ( β 1 , β 3 and α ) and dopaminergic (D 2 ) receptors are reported. Poor subtype selectivity at the muscarinic receptors is a general feature of anti-muscarinics (Tiotropium, e.g., is essentially equipotent at M 1 , M 2 and M 3 ) and, therefore, a truly selective M 3 MABA is likely to be both difficult to achieve and not required from a safety standpoint. The required selectivity profile against the other β -adrenergic receptors is not clearly defined; the long-acting β -agonist salmeterol has the best β 2 / β 1 selectivity profile of the current long-acting β -agonists, but demonstrates cardio-vascular side effects in humans [43] . Two recent studies have served to underline the safety of muscarinic antagonists and β -agonists in the treatment of COPD: the UPLIFT study [44] showed no evidence of increased cardiovascular death, myocardial infarction or stroke in COPD patients treated with tiotropium, and [45] no increased risk of respiratory

death for patients taking LABAs in comparison with placebo. How the safety profile of MABAs compares has started to be disclosed: data provided in [12] showed a change in heart rate comparable with, or lower than, salmeterol b.i.d. + tiotropium q.i.d.

The earlier applications often contain broad definitions for the linking group, but in applications such as [40] where both M 3 and β 2 data are presented for compounds, it can be noted that the linking group has effects on both M 3 and β 2 activities, both in terms of absolute potencies at the two pharmacologies, and the relative potencies between them. It is likely that this will become an area for further investigation. Perhaps the major challenge still to be addressed is in defining the correct balance of activity of the two pharmacologies in man: the Theravance clinical data provide some first insights into this key aspect.

Declaration of interest

NC Ray is an employee of Argenta Discovery Ltd and L Alcaraz is an employee of AstraZeneca R&D Ltd.

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12. Theravance Press release (last checked September 2008) Available from: http://ir.theravance.com/ReleaseDetail.cfm?ReleaseID = 322048

13. Morphy R, Rankovic Z. The Physicochemical Challenges of Designing Multiple Ligands. J Med Chem 2006 ; 49 : 4961 -70. and Designed Multiple Ligands. J Med Chem 2005;48:6523-43

14. Yamanouchi. WO1995021820. See also Naito R, Takeuchi M, Morihira K, et al. Selective muscarinic antagonists. I. Synthesis and antimuscarinic properties of biphenylcarbamate derivatives. Chem Pharm Bull 1998 ; 46 : 1274 -85

15. Theravance, Inc. WO04074246




19. ClinTrials.Gov website (last checked September 2008). Available from: http://clinicaltrials.gov/ct2/show/NCT00550225?term = GSK961081&rank = 3




23. Bonnert RV, Brown RC, et al. Dual D2-Receptor and β 2-Adrenoceptor agonists for the treatment of airway diseases. 1. Discovery and biological evaluation of some 7-(2-Aminoethyl)-4-hydroxybenzothiazol-2(3H )-one analogues. J Med Chem 1998 ; 41 : 4915 -7

24. Theravance, Inc. WO06023457. See also Norman P. Dual-acting β 2 agonists/muscarinic antagonists. Expert Opin Ther Patents 2006 ; 16 : 1327 -31






30. See Argenta Discovery website, last checked 25/09/08. Available from: http://www.argentadiscovery.com/news/press_releases/archive/310107_argenta_astrazeneca.html

31. Argenta Discovery. WO07017669


33. Argenta Discovery/AstraZeneca. WO08023157





38. Boehringer-Ingelheim Corp. US20050256114

39. Novartis. AG. WO08000483

40. Pfi zer, Inc. WO07107828

41. See for example WO05080324. Pfi zer Inc. as an example of Pfi zer’s β 2 -agonist patent estate containing the arylsulfonamide motif

42. Pfi zer, Inc. WO08041095

43. Motomura S, Reinhard-Zerkowski H, Daul A, et al. On the physiological role of beta-2 receptors in the human heart: in vitro and in vivo studies. Am Heart J 1990 ; 119 : 608 -19

44. Tashkin DP, Celli B, Senn S, et al. A four year trial of tiotropium in chronic obstructive pulmonary disease. N Engl J Med 2008 ; 359 (15): 1616 -8

45. Rodrigo GJ, Nannini LJ, Rodríguez-Roisin R. Safety of long-acting beta-agonists in COPD: a systematic review. Chest 2008 ; 133 (5): 1079 -87

Affi liation Nicholas C Ray † 1 PhD & Lilian Alcaraz 2 PhD † Author for correspondence 1 Argenta Discovery Ltd, 8-9 Spire Green Centre, Flex Meadow, Essex CM19 5TR, Harlow, UK Tel: +44 0 1279 645645 ; Fax: +44 0 1279 645646 ; E-mail: [email protected] 2 AstraZeneca R&D Charnwood, Bakewell Road, Loughborough, LE11 5RH, Leicestershire, UK

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Muscarinic antagonist-β-adrenergic agonist dual pharmacology molecules as bronchodilators: a patent...

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