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

  • J Med Chem. 2018 Sep 27;61(18):8186-8201. doi: 10.1021/acs.jmedchem.8b00518.
Daniel B Horne ,  Kaustav Biswas ,  James Brown ,  Michael D Bartberger ,  Jeffrey Clarine ,  Carl D Davis ,  Vijay K Gore ,  Scott Harried ,  Michelle Horner ,  Matthew R Kaller ,  Sonya G Lehto ,  Qingyian Liu ,  Vu V Ma ,  Holger Monenschein ,  Thomas T Nguyen ,  Chester C Yuan ,  Beth D Youngblood ,  Maosheng Zhang ,  Wenge Zhong ,  Jennifer R Allen ,  Jian Jeffrey Chen ,  Narender R Gavva
PMID: 30148953 DOI: 10.1021/acs.jmedchem.8b00518
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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