Novel α6gaba A R Subtype-Selective Ligands for CNS Disorders and Trigeminal Pain

Transcription

1 Novel α6gaba A R Subtype-Selective Ligands for CNS Disorders and Trigeminal Pain (OTT1410) Joint Inventors From: UW-Milwaukee, Medical University of Vienna, TU Wien, University of Belgrade, and National Taiwan University For further information please contact: Jessica Silvaggi, PhD, CLP Senior Licensing Manager 1440 East North Ave. Milwaukee, WI Tel: Jessica@uwmrf.org UWMRF

2 Current Problems with CNS Drugs Many GABAergic drugs on the market today offer little selectivity towards various subtypes of GABA A 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 UWMRF

3 Our Solution: Novel α6gaba A R ligands Recently, the α6 subunit-containing GABA A receptor (α6gaba A R) has been implicated in neuropsychiatric disorders with sensorimotor gating deficits, migraine, orofacial pain and depression. α6gaba A R-selective positive allosteric modulators (α6gaba A R PAMs) First-in-Class: First ligands highly selective to α6gaba A Rs Functionally Selective: silent at α1- and α5-gaba A Rs 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 UWMRF

4 Intellectual Property and Licensing PCT/US2016/ 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 UWMRF

5 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 UWMRF

6 GABA A Receptors: Established Drug Targets 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 α6gaba A R have been found to be located in the cerebellum and trigeminal ganglia Compounds targeting α6gaba A Rs can rescue a disrupted pre-pulse inhibition (PPI), which is a common endophenotype manifestation present in many neuropsychiatric disorders UWMRF

7 The GABA A Receptor (GABA A R) α6β3γ2 The GABA A R 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, UWMRF

8 GABA A R α6β3γ2 subtype selectivity UWMRF

9 Analogs retain activity at the α6gaba A R Deuterated and N-Hetero analogs retained activity at the α6gaba A R UWMRF

10 Improvement of Metabolic Stability Metabolic Stability t1/2 HLM t1/2 MLM Pharmacokinetics Ligand CMAX t1/2 CMAX t1/2 Plasma Plasma Brain Brain (h) (h) (ng / ml) (h) (ng / g) (h) PZ-II ± ± ± ± ± ± 0.37 DK-I ± ± ± ± ± ± 0.32 RV-I ± ± ± ± ± ± 0.27 DK-I ± ± ± ± ± ± 0.71 DK-I ± ± ± ± ± ± 5.45 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) UWMRF

11 Pre-pulse inhibition of the Startle response (PPI) 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 UWMRF Geyer et al., Mol Psychiatry. (2002) 7:1039

12 PPI (%) α6gaba A R PAMs rescued the PPI impairment PPI (%) db db METH 2 mg/kg METH 2 mg/kg db METH 2 mg/kg db METH 2 mg/kg 60 # ## 60 # # 40 *** *** 40 ## ## ## *** *** Compound 6 LAU 159 LAU 463 I-29 Vehicle Vehicle Compound 6 LAU 159 LAU 463 I-29 Compound 6 LAU 159 LAU 463 I-29 Vehicle Vehicle Compound 6 LAU 159 LAU 463 I-29 0 Vehicle DK-I-56-1 DK-I-59-1 DK-I-58-1 Vehicle DK-I-56-1 DK-I-59-1 DK-I-58-1 Vehicle DK-I-56-1 DK-I-59-1 DK-I-58-1 Vehicle DK-I-56-1 DK-I-59-1 DK-I-58-1 Mouse model mimicking schizophrenia based on the hyper-dopaminergic hypothesis Methamphetamine (METH), a hyperdopaminergic agent, significantly disrupted PPI induced by two protocols ( db and db) in mice All α6gaba A R PAMs (10 mg/kg) effectively rescued the METH disruption of PPI UWMRF

13 The furosemide-sensitive effects of α6gaba A R PAMs Prepulse inhibition (%) db db Methamphetamine 2 mg/kg 60 Methamphetamine 2 mg/kg ** ** 40 ** && ** &&& *** *** *** &&& *** && *** *** 20 0 Furo Furo Furo Furo Furo Furo Vehicle C6 C11 Vehicle C6 C11 Two α6gaba A R PAMs (C6 and C11) significantly rescued METH-induced PPI disruptions Furosemide, an α6gaba A R-selective antagonist, blocked their effects, confirming α6gaba A R as the action target UWMRF

14 Reduction of Trigeminal Neuropathic Pain Two-week repeated treatment with DK-I-56-1 in a rat model of trigeminal neuropathy can provide both, a preventive and a therapeutic effect on neuropathic pain (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 or placebo (days 15 to 28) to rats with the already existing trigeminal neuropathy, with (D) respective scores of reactivity to von Frey filaments UWMRF

15 Cpd 6 Performs Similar to Clinical Migraine Agent Trigemino-cervical complex (TCC) Trigeminal ganglia (TG) Dura mater 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 UWMRF

16 Toxicity and Drug Potential Assays BZP Rat Brain Radioligand % Inhibition Cytotoxicity Ligand Site Binding BZP Rat herg HEK293 (Kidney) HEPG2 (Liver) Affinity (nm) Brain Site Channel LD50 (µm) LD50 (µm) PZ-II NA NA DK-I >400 >400 RV-I >400 >200 DK-I >400 >400 DK-I >400 >400 GABA A R 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 UWMRF

17 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 UWMRF

18 Acknowledgements and Collaborations Acknowledgements and Collaborations Marco Treven & Zdravko Varagic Margot Ernst & Werner Sieghart Branka Divovic & Vladimir Dobricic Miroslav Savic Pi-Chuan Fan Lih-Chu Chiou Daniel Knutson & Revathi Kodali Laurin Wimmer & David Siebert Nicholas Zahn & Alec Huber Marko D. Mihovilovic Michael Rajesh Stephen Ranjit Verma, Christopher Witzigmann & Matheus Meirelles Alexander Arnold & James Cook Brian Roth UWMRF