Design, synthesis, and biological evaluation of novel biphenyl-4-carboxamide derivatives as orally available TRPV1 antagonists. Issue 12 (23rd July 2018)

• Record Type: Journal Article
• Authors: Oka, Hiromasa; Yonezawa, Koichi; Kamikawa, Akio; Ikegai, Kazuhiro; Asai, Norio; Shirakami, Shohei; Miyamoto, Satoshi; Watanabe, Toshihiro; Kiso, Tetsuo; Takemoto, Yukihiro; Tamura, Seiji; Kuramochi, Takahiro
• Is Part Of: Bioorganic & medicinal chemistry. Volume 26:Issue 12(2018)
• Page Start: 3716
• Page End: 3726
• Publication Date: 2018-07-23
• Subjects: TRPV1 antagonist -- Neuropathic pain -- Agonist -- Biphenyl-4-carboxamide -- Oral absorption; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2018.06.001
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: 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.