Discovery of TRPM8 Antagonist ( S)-6-(((3-Fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)carbamoyl)nicotinic Acid (AMG 333), a Clinical Candidate for the Treatment of Migraine

Journal of Medicinal Chemistry
Daniel B HorneNarender R Gavva

Abstract

Transient-receptor-potential melastatin 8 (TRPM8), the predominant mammalian cold-temperature thermosensor, is a nonselective cation channel expressed in a subpopulation of sensory neurons in the peripheral nervous system, including nerve circuitry implicated in migraine pathogenesis: the trigeminal and pterygopalatine ganglia. Genomewide association studies have identified an association between TRPM8 and reduced risk of migraine. This disclosure focuses on medicinal-chemistry efforts to improve the druglike properties of initial leads, particularly removal of CYP3A4-induction liability and improvement of pharmacokinetic properties. A novel series of biarylmethanamide TRPM8 antagonists was developed, and a subset of leads were evaluated in preclinical toxicology studies to identify a clinical candidate with an acceptable preclinical safety profile leading to clinical candidate AMG 333, a potent and highly selective antagonist of TRPM8 that was evaluated in human clinical trials.

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Citations

May 31, 2019·International Journal of Molecular Sciences·Rosario González-MuñizIsabel Gómez-Monterrey
Sep 2, 2020·Neuroscience Bulletin·Mamoru Shibata, Chunhua Tang
Sep 18, 2020·Expert Opinion on Investigational Drugs·Asia Fernández-CarvajalAntonio Ferrer-Montiel
Apr 12, 2019·Pharmaceuticals·Silvia Benemei, Greg Dussor
Aug 28, 2020·Scientific Reports·M Ángeles BonacheRosario González-Muñiz
Jul 2, 2020·European Journal of Pharmacology·Yuqian LiuXiaohui Zhou
Mar 7, 2021·International Journal of Molecular Sciences·María Ángeles BonacheRosario González-Muñiz
Aug 28, 2021·International Journal of Molecular Sciences·Carolina IzquierdoRosario González-Muñiz
Sep 17, 2021·Nature Reviews. Drug Discovery·Ari-Pekka KoivistoArpad Szallasi

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