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-oxobicyclo[5.4.0]undeca-1(7),8,10-triene derivatives exhibited antagonistic activity for vasopressin V 1 and V 2 receptors. Most of these compounds were synthesized and showed a high affinity potential for V 2 receptor and low to moderate affinity potential for V, receptor. The most potent and V 2 -selective compound, N-[4-12,6-diaza-6-[2-(4-methylpiperazinyl)-2-oxoethyl]-5-oxobicyclo[5.4.0]undeca-1(7),8,10-trien-2-yl]-carbonyl]phenyl][2-(4-methylphenyl)phenyl]-formamide (11b), exhibited IC 50 's of 2.9 nM for the V 2 receptor and 200 nM for the V 1 receptor, respectively. When administered orally to rat, 11b showed an approximately 18-fold increased urine volume in comparison with control rat.