Q1 · MEDICINE
Article
Author: Kaller, Matthew R. ; Liu, Qingyian ; Davis, Carl D. ; Nguyen, Thomas T. ; Ma, Vu V. ; Clarine, Jeffrey ; Lehto, Sonya G. ; Zhang, Maosheng ; Gore, Vijay K. ; Monenschein, Holger ; Chen, Jian Jeffrey ; Brown, James ; Horne, Daniel B. ; Harried, Scott ; Youngblood, Beth D. ; Zhong, Wenge ; Biswas, Kaustav ; Yuan, Chester C. ; Gavva, Narender R. ; Allen, Jennifer R. ; Horner, Michelle ; Bartberger, Michael D.
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.