Discovery of 4,5-Diphenyl-1,2,4-triazole Derivatives as a Novel Class of Selective Antagonists for the Human V1A Receptor Original Research Article

In the search for a novel class of selective antagonists for the human V1A receptor, high-throughput screening (HTS) of the Yamanouchi chemical library using CHO cells expressing the cloned human V1A (hV1A) receptor led to the discovery of 5-(4-biphenyl)-4-(2-methoxyphenyl)-3-methyl-1,2,4-triazole (3) which possessed the novel 4,5-diphenyl-1,2,4-triazole structure. Subsequent structure–activity relationships studies on a series of the 4,5-diphenyl-1,2,4-triazole derivatives related to 3 revealed that the 4,5-diphenyl-1,2,4-triazole structure played an essential role in exerting high affinity for the hV1A receptor and that introduction of a basic amine moiety to the methoxy part of the 4-phenyl ring was effective in the improvement of both affinity for the hV1A receptor and selectivity versus the hV2 receptor. Compound 3 and the 2-(morphorino)ethoxy derivative (11b) were shown to be antagonists for the hV1A receptor, from their effects on AVP-induced [Ca2+]i response in CHO cells expressing the hV1A receptor.