2,5-Disubstituted 3,4-dihydro-2H-benzo[b][1,4]thiazepines as potent and selective V2 arginine vasopressin receptor antagonists

• Published in: Bioorganic & medicinal chemistry letters 2003-11, Vol.13 (22), p.4031-4034
• Main Authors: URBANSKI, Maud J, CHEN, Robert H, DEMAREST, Keith T, GUNNET, Joseph, LOOK, Richard, ERICSON, Eric, MURRAY, William V, RYBCZYNSKI, Philip J, XIAOYAN ZHANG
• Format: Article
• Language: English
• Subjects: Animals; Antidiuretic Hormone Receptor Antagonists; Azepines - chemical synthesis; Azepines - chemistry; Azepines - pharmacology; Benzamides - chemical synthesis; Benzamides - chemistry; Benzamides - pharmacology; Benzazepines - chemical synthesis; Benzazepines - chemistry; Benzazepines - pharmacology; Biological and medical sciences; Dibenzothiazepines - chemical synthesis; Dibenzothiazepines - pharmacology; Diuresis - drug effects; Drug Design; Kinetics; Male; Medical sciences; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems; Pharmacology. Drug treatments; Pyrroles; Rats; Structure-Activity Relationship
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2003.08.051

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.