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.

中文翻译：

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发现TRPM8拮抗剂（S）-6-（（（（3-氟4-（三氟甲氧基）苯基）（3-氟吡啶-2-基-2-基）甲基）氨基甲酰基）烟酸（AMG 333），这是一种临床候选药物偏头痛

瞬态受体潜力褪黑素8（TRPM8）是哺乳动物的主要低温温度传感器，是一种非选择性阳离子通道，在周围神经系统的感觉神经元亚群中表达，包括与偏头痛发病有关的神经回路：三叉神经和翼pt神经节。全基因组关联研究已确定TRPM8与偏头痛风险降低之间的关联。本公开内容集中于药物化学上的努力，以改善初始导联的药物样性质，特别是去除CYP3A4诱导作用和改善药代动力学性质。开发了一系列新颖的联芳基甲酰胺TRPM8拮抗剂，