2. Academic Validation
  3. 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

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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