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.
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| 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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| Authors | 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 |
| Journal | Journal of medicinal chemistry (J Med Chem) Vol. 61 Issue 18 Pg. 8186-8201 (09 27 2018) ISSN: 1520-4804 [Electronic] United States |
| PMID | 30148953 (Publication Type: Journal Article) |
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