
Journal of Medicinal Chemistry p. 8186 - 8201 (2018)
Update date:2022-08-15
Topics:
Horne, Daniel B.
Biswas, Kaustav
Brown, James
Bartberger, Michael D.
Clarine, Jeffrey
Davis, Carl D.
Gore, Vijay K.
Harried, Scott
Horner, Michelle
Kaller, Matthew R.
Lehto, Sonya G.
Liu, Qingyian
Ma, Vu V.
Monenschein, Holger
Nguyen, Thomas T.
Yuan, Chester C.
Youngblood, Beth D.
Zhang, Maosheng
Zhong, Wenge
Allen, Jennifer R.
Chen, Jian Jeffrey
Gavva, Narender R.
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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