1416946-01-4Relevant academic research and scientific papers
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
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.
, p. 8186 - 8201 (2018/09/21)
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.
TRPM8 ANTAGONISTS AND THEIR USE IN TREATMENTS
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Page/Page column 185; 189, (2013/02/28)
Compounds of Formula (I) are useful as antagonists of TRPM8. Such compounds are useful in treating a number of TRPM8 mediated disorders and conditions and may be used to prepare medicaments and pharmaceutical compositions useful for treating such disorders and conditions. Examples of such disorders include, but are not limited to, migraines and neuropathic pain. Compounds of Formula (I) have the above structure, where the definitions of the variables are provided herein.
