Novel α6GABAAR Subtype-Selective Ligands for CNS Disorders ... · • Global migraine sales are...

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1/25/18 ©UWMRF 2018 1 Joint Inventors From: UW-Milwaukee, Medical University of Vienna, TU Wien, University of Belgrade, and National Taiwan University Novel α6GABA A R Subtype-Selective Ligands for CNS Disorders and Trigeminal Pain (OTT1410) For further information please contact: Jessica Silvaggi, PhD, CLP Senior Licensing Manager 1440 East North Ave. Milwaukee, WI 53202 Tel: 414-906-4654 [email protected]g
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Transcript of Novel α6GABAAR Subtype-Selective Ligands for CNS Disorders ... · • Global migraine sales are...

  • 1/25/18©UWMRF 2018 1

    Joint Inventors From:

    UW-Milwaukee, Medical University of Vienna, TU Wien,

    University of Belgrade, and National Taiwan University

    Novel α6GABAAR Subtype-Selective Ligands for CNS Disorders and

    Trigeminal Pain(OTT1410)

    For further information please contact:

    Jessica Silvaggi, PhD, CLP

    Senior Licensing Manager

    1440 East North Ave. Milwaukee, WI 53202

    Tel: 414-906-4654

    [email protected]

  • Current Problems with CNS Drugs

    • Many GABAergic drugs on the market today offer little selectivity towards various subtypes of GABAA receptors, and thus exhibit undesired side effects

    • These include sedation, ataxia, amnesia, tolerance, and addiction

    • There has been a lack of new drugs developed for CNS disorders, while the social, clinical, and economic needs are growing

    1/25/18©UWMRF 2018 2

  • Our Solution: Novel α6GABAAR ligands

    Recently, the α6 subunit-containing GABAA receptor (α6GABAAR) has been implicated in neuropsychiatric disorders with sensorimotor gating deficits, migraine, orofacial pain and depression.

    • α6GABAAR-selective positive allosteric modulators (α6GABAAR PAMs)

    – First-in-Class: First ligands highly selective to α6GABAARs

    – Functionally Selective: silent at α1- and α5-GABAARs

    • Devoid of sedative, motor-impairing, amnesia side effect

    • Should be no tolerance and non-addictive

    – Effective: Promising results in animal models for several indications

    – Pharmacokinetic profiles: Lead compounds show

    • Good metabolic stability (in vitro)

    • Excellent bioavailability (oral)

    • Appropriate brain concentrations (oral)

    – Safe: Lead compounds show a lack of liver or kidney toxicity

    1/25/18©UWMRF 2018 3

  • • PCT/US2016/035761 nationalized Fall/Winter 2017

    • U.S. Utility Patent Pending

    • EP Patent Pending

    Looking for a development partner to:

    • Provide support for follow up animal testing in lead compounds

    • Aid in moving towards the regulatory approval process and IND filing

    • License the technology for development of new drugs

    1/25/18©UWMRF 2018 4

    Intellectual Property and Licensing

    https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2016196961

  • Market Potential

    Potential Applications

    • Neuropsychiatric disorders with sensorimotor gating deficits

    – Schizophrenia

    – Tic disorders (Tourette’s syndrome), Obsessive compulsive disorder, Attention deficit disorders

    – Panic disorder, Nocturnal enuresis, Antisocial personality disorder, Mania, Premenstrual dysphoric disorder, Huntington’s disease

    • Depression

    • Trigeminal pain: Migraine, Trigeminal orofacial pain

    Market

    • 45% of people will be affected by some type of neuropsychiatric disorder

    • Global migraine sales are expected to grow to $8.7 billion by 2026, however current treatments leave a large number of patients undertreated

    • The global temporomandibular joint (TMJ) disorders market is expected to reach $1.2B by 2023, while the CNS therapeutic market is expected to reach $128.9 billion by 2025

    • Response rate to off-label use of drugs in post-traumatic trigeminal neuropathy is around 11%; the need is urgent for more efficient and tolerable drugs

    1/25/18©UWMRF 2018 5

  • GABAA Receptors: Established Drug Targets

    1/25/18©UWMRF 2018 6

    • Chloride ion channel

    • Well characterized CNS activity

    • Positive modulators work at allosteric sites and increase channel efficacy

    • Receptor is readily druggable; approved small molecule drugs in wide-spread clinical use

    • α6GABAAR have been found to be located in the cerebellum and trigeminal ganglia

    • Compounds targeting α6GABAARs can rescue a disrupted pre-pulse inhibition (PPI), which is a common endophenotype manifestation present in many neuropsychiatric disorders

  • The GABAA Receptor (GABAAR) α6β3γ2

    1/25/18©UWMRF 2018 7

    • The GABAAR α6β3γ2 subtype is a pentameric ligand-gated chloride channel comprised of two α6, two β3 and one γ2 subunit

    • Pyrazoloquinolinones mediate their effects at the α6+β3- interface (PQ Site) as positive allosteric modulators and act at the diazepam insensitive benzodiazepine (DI-Bz) site (α6+γ2-interface) as null modulators

    • The PQ site, the DI binding site and the endogenous ligand (GABA) binding sites at the β3+α6- interfaces are displayed

    Image modified from Jacob et al., Nature Reviews Neuroscience, 2008.

  • GABAAR α6β3γ2 subtype selectivity

    1/25/18©UWMRF 2018 8 8

  • 9

    Deuterated and N-Hetero analogs retained activity at the α6GABAAR

    1/25/18©UWMRF 2018

    Analogs retain activity at the α6GABAAR

  • 10

    Ligand

    Metabolic Stability Pharmacokinetics

    t1/2 HLM (h)

    t1/2 MLM

    (h)

    CMAX Plasma

    (ng / mL)

    t1/2 Plasma

    (h)

    CMAX Brain

    (ng / g)

    t1/2 Brain

    (h)

    PZ-II-029 3.6 ± 0.6 3.2 ± 0.1 5050 ± 770 1.51 ± 0.04 352 ± 17 1.96 ± 0.37

    DK-I-56-1 8.7 ± 0.6 10.5 ± 0.9 4430 ± 320 3.54 ± 0.71 589 ± 93 2.28 ± 0.32

    RV-I-029 11.1 ± 3.6 14.3 ± 2.8 3740 ± 390 2.46 ± 0.15 657 ± 71 2.60 ± 0.27

    DK-I-60-3 13.0 ± 2.9 14.1 ± 3.3 3410 ± 250 2.64 ± 0.54 534 ± 14 3.52 ± 0.71

    DK-I-86-1 12.5 ± 3.1 9.2 ± 0.9 1250 ± 80 17.99 ± 15.48 215 ± 23 9.07 ± 5.45

    Improvement of Metabolic Stability

    • OCD3 and N-hetero Substitution Improved Metabolic Stability and Pharmacokinetic Profile• Deuteration of A or D-ring methoxy group increased the metabolic stability• N-Hetero introduction into D-ring also increased the metabolic stability• Only deuterated compounds exhibited enhanced bioavailability (Cmax, Brain)

    1/25/18©UWMRF 2018

  • Pre-pulse inhibition of the Startle response (PPI)

    Geyer et al., Mol Psychiatry. (2002) 7:1039

    PPI: A weaker pre-stimulus (pre-pulse) inhibits the reaction (startle response) of an organism to a subsequent strong startling stimulus (pulse), a measurement of sensorimotor gating function

    1/25/18©UWMRF 2018 11

  • • Mouse model mimicking schizophrenia based on the hyper-dopaminergic hypothesis

    • Methamphetamine (METH), a hyperdopaminergic agent, significantly disrupted PPI induced by two protocols (71-115 dB and 77-115 dB) in mice

    • All α6GABAAR PAMs (10 mg/kg) effectively rescued the METH disruption of PPI

    1/25/18©UWMRF 2018 12

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    )α6GABAAR PAMs rescued the PPI impairment

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    Furo Furo Furo Furo Furo Furo

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    • Two α6GABAAR PAMs (C6 and C11) significantly rescued METH-induced PPI disruptions

    • Furosemide, an α6GABAAR-selective antagonist, blocked their effects, confirming α6GABAAR as the action target

    The furosemide-sensitive effects of α6GABAAR PAMs

    1/25/18©UWMRF 2018 13

  • Reduction of Trigeminal Neuropathic Pain

    1/25/18©UWMRF 2018 14

    (A) Injections of 10mg/kg DK-I-56-1 or placebo (days 1 to 14) to rats subjected to ligature of the infraorbital nerve or sham surgery, with(B) respective scores of reactivity to von Frey filaments(C) Injections of 10mg/kg DK-I-56-1, 10mg/kg DK-I-87-1 or placebo (days 15 to 28) to rats with the already existing trigeminal neuropathy, with(D) respective scores of reactivity to von Frey filaments

    Two-week repeated treatment with DK-I-56-1 in a rat model of trigeminal neuropathycan provide both, a preventive and a therapeutic effect on neuropathic pain

  • • Capsaicin-induced migraine model; topiramate (TPM) is a clinically effective anti-migraine agent, and was used as a positive control

    • Compound 6 significantly decreased the number of c-Fos-ir neurons in the TCC and CGRP-ir in TG induced by capsaicin

    • Compound 6 reversed capsaicin-induced depletion of dural CGRP-ir

    • Suggests potential for migraine treatment

    1/25/18©UWMRF 2018 15

    Trigemino-cervical complex (TCC) Trigeminal ganglia (TG) Dura mater

    Cpd 6 Performs Similar to Clinical Migraine Agent

  • Toxicity and Drug Potential Assays

    16

    • GABAAR binding >1000 fold higher than all “off target” receptors (46) tested

    • Ligands are non-toxic to kidney and liver cells even at 400 µM

    • Studies of locomotion on the rotarod confirmed that ligands are not sedating or ataxic in models Rotarod Device

    Ligand BZP Rat Brain Site Binding Affinity (nM)

    Radioligand % Inhibition Cytotoxicity

    BZP Rat Brain Site

    hERG Channel

    HEK293 (Kidney) LD50 (µM)

    HEPG2 (Liver) LD50 (µM)

    PZ-II-029 2.7 92.4 7.4 NA NA

    DK-I-56-1 2.1 96.2 0.1 >400 >400

    RV-I-029 2.0 96.7 6.9 >400 >200

    DK-I-60-3 2.3 94.5 8.7 >400 >400

    DK-I-86-1 21.7 98.2 8.6 >400 >400

    1/25/18©UWMRF 2018

  • Next Steps

    • ~$700,000 in funding needed to conduct further experiments on animal models mimicking Tourette syndrome, trigeminal pain, depression, and tinnitus.

    • In need of collaborations to conduct drug development in preclinical studies in the safety pharmacology, toxicology assessments, and pharmacokinetic studies

    1/25/18©UWMRF 2018 17

  • Acknowledgements and Collaborations

    Daniel Knutson & Revathi KodaliNicholas Zahn & Alec Huber

    Michael Rajesh StephenRanjit Verma, Christopher Witzigmann & Matheus Meirelles

    Alexander Arnold & James Cook

    18

    Brian Roth

    Pi-Chuan Fan

    Lih-Chu ChiouMarco Treven & Zdravko Varagic

    Margot Ernst & Werner SieghartBranka Divovic & Vladimir Dobricic

    Miroslav Savic

    Acknowledgements and Collaborations

    Laurin Wimmer & David Siebert

    Marko D. Mihovilovic

    1/25/18©UWMRF 2018