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