Synthesis and characterization of orally active nonpeptide vasopressin V2 receptor antagonists.

The present study was undertaken to evaluate whether a novel series of 2,6-diaza-5-oxobicyclo5.4.0]undeca-1(7),8,10-triene derivatives exhibited antagonistic activity for vasopressin V1 and V2 receptors. Most of these compounds were synthesized and showed a high affinity potential for V2 receptor and low to moderate affinity potential for V1 receptor. The most potent and V2-selective compound, N-4-2,6-diaza-6-2-(4-methylpiperazinyl)-2-oxoethyl] -5- oxobicyclo5.4.0]undeca-1(7),8,10-trien-2-yl]-carbonyl]pheny l]2-(4- methylphenyl)phenyl]-formamide (11b), exhibited IC50's of 2.9 nM for the V2 receptor and 200 nM for the V1 receptor, respectively. When administered orally to rat, 11b showed an approximately 18-fold increased urine volume in comparison with control rat.