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 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.
Urbanski
Maud J
MJ
Drug Discovery, Johnson & Johnson Pharmaceutical Research & Development L.L.C., 1000 Route 202, Raritan, NJ 08869-0602, USA. murbansk@prdus.jnj.com
Chen
Robert H
RH
Demarest
Keith T
KT
Gunnet
Joseph
J
Look
Richard
R
Ericson
Eric
E
Murray
William V
WV
Rybczynski
Philip J
PJ
Zhang
Xiaoyan
X
D000818:Animals; D065092:Antidiuretic Hormone Receptor Antagonists; D001381:Azepines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001549:Benzamides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001552:Benzazepines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D003987:Dibenzothiazepines / Q000138:chemical synthesis* / Q000494:pharmacology*; D004231:Diuresis / Q000187:drug effects; D015195:Drug Design; D007700:Kinetics; D008297:Male; D011758:Pyrroles; D051381:Rats; D013329:Structure-Activity Relationship; D001569:Benzodiazepines
D065092:Antidiuretic Hormone Receptor Antagonists; D001381:Azepines; D001549:Benzamides; D001552:Benzazepines; D003987:Dibenzothiazepines; D011758:Pyrroles; C106389:conivaptan; C076251:mozavaptan; C409452:lixivaptan; D001569:Benzodiazepines