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

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...

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Bibliographic Details
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
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Summary: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.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2003.08.051