Synthesis and pharmacological evaluation of 5-(4-biphenyl)-3-methyl-4-phenyl-1,2,4-triazole derivatives as a novel class of selective antagonists for the human vasopressin V1a receptor

Article abstract of DOI:10.1021/jm010544r

A series of 5-(4-biphenyl)-3-methyl-4-phenyl-1,2,4-triazole derivatives were prepared and evaluated as selective antagonists for the human vasopressin V_1A receptor. The compounds were examined for their affinity to the cloned human V_1A receptor (hV_1A) and selectivity vs the cloned human V₂ receptor (hV₂). By utilizing the structure-activity relationship on 4,4-difluoro-5-methylidene-2,3,4,5-tetrahydrobenzazepine derivatives as dual antagonists for the V_1A and V₂ receptors in our previous study, we found that substituting the methoxy group at the 2-position of the 4-phenyl ring with (4-methylpiperazin-1-yl)alkoxy moieties brought about marked improvement of both affinity to hV_1A and selectivity vs hV₂. Further introduction of a methyl group into the 6-position of the 4-phenyl ring resulted in additional improvement of selectivity. One particular compound, 5-(4-biphenyl)-3-methyl-4-{2-[6-(4-methyl-l-piperazinyl)-hexyloxy]phenyl} -1,2,4-triazole (19) showed potent affinity to hV_1A with a K_i value of 1.04 nM and high selectivity with a 1700-fold selectivity vs hV₂. We also found marked differences in the affinity of compounds in this series between the human and the rat receptors. Compound, 19 was further examined for its V_1A receptor antagonist activity in rats. As a result, 19 demonstrated antagonist activities toward an arginine vasopressin-induced increase in diastolic blood pressure after intravenous or oral administration and long-lasting oral activity.