2,5-Disubstituted 3,4-Dihydro-2H-benzo[b][1,4]thiazepines as Potent and Selective V2 Arginine Vasopressin Receptor Antagonists.

Abstract A number of 2,5-disubstituted benzothiazepines were synthesized and screened for their ability to inhibit arginine vasopressin binding to the human V 2 and V 1a receptor subtypes. The more active compounds were subsequently analyzed for their antagonist activity in in vitro functional assays. The SAR showed a preference for an acidic unit appended from the benzothiazepine scaffold. This substitution pattern afforded the most potent and selective analogues in the series. The carboxymethyl analogue 4 , showed a 140-fold greater selectivity for the V 2 over the V 1a receptor in the binding assay. In the cell-based functional assays this analogue was a potent and selective antagonist of the V 2 receptor. The in vitro SAR of the series and a description of the in vivo studies around compound 4 is described.