Design, synthesis, and biological evaluation of novel biphenyl-4-carboxamide derivatives as orally available TRPV1 antagonists

Publication date: Available online 2 June 2018
Source:Bioorganic & Medicinal Chemistry
Author(s): Hiromasa Oka, Koichi Yonezawa, Akio Kamikawa, Kazuhiro Ikegai, Norio Asai, Shohei Shirakami, Satoshi Miyamoto, Toshihiro Watanabe, Tetsuo Kiso, Yukihiro Takemoto, Seiji Tamura, Takahiro Kuramochi
A new series of transient receptor potential vanilloid type 1 (TRPV1) antagonists were designed and synthesized from N-(3-hydroxyphenyl)-2-(piperidin-1-ylmethyl)biphenyl-4-carboxamide hydrochloride (8). SAR studies identified (R)-N-(1-methyl-2-oxo-1,2,3,4-tetrahydro-7-quinolyl)-2-[(2-methylpyrrolidin-1-yl)methyl]biphenyl-4-carboxamide hydrochloride (ASP8370, 7), as a compound with high aqueous solubility, satisfactory stability in human liver microsomes, and reduced CYP3A4 inhibition. ASP8370 was selected as a clinical development candidate with significant ameliorative effects on neuropathic pain. SAR studies also revealed the structural mechanisms underlying the switching between TRPV1 antagonism and agonism.

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