Aminomethylpiperazines as selective urotensin antagonists.
Aminomethylpiperazines, reported previously as being kappa-opioid receptor agonists, were identified as lead compounds in the development of selective urotensin receptor antagonists. Optimized substitution of the piperazine moiety has provided high affinity urotensin receptor antagonists with greater than 100-fold selectivity over the kappa-opioid receptor. Select compounds were found to inhibit urotensin-induced vasoconstriction in isolated rat aortic rings consistent with the hypothesis that an urotensin antagonist may be useful for the treatment of hypertension.
Hilfiker
Mark A
MA
Department of Medicinal Chemistry, Cardiovascular and Urogenital Center of Excellence for Drug Discovery, GlaxoSmithKline Pharmaceuticals, 709 Swedeland Road, PO Box 1539, King of Prussia, PA 19406, USA. mark.a.hilfiker@gsk.com
Zhang
Daohua
D
Dowdell
Sarah E
SE
Goodman
Krista B
KB
McAtee
John J
JJ
Dodson
Jason W
JW
Viet
Andrew Q
AQ
Wang
Gren Z
GZ
Sehon
Clark A
CA
Behm
David J
DJ
Wu
Zining
Z
Carballo
Luz H
LH
Douglas
Stephen A
SA
Neeb
Michael J
MJ
D000077443:Acamprosate; D000818:Animals; D001011:Aorta / Q000378:metabolism; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D015195:Drug Design; D006801:Humans; D006973:Hypertension / Q000188:drug therapy; D008956:Models, Chemical; D010879:Piperazines / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017473:Receptors, Opioid, kappa / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D013654:Taurine / Q000031:analogs & derivatives* / Q000187:drug effects; D014579:Urotensins / Q000037:antagonists & inhibitors*
D010879:Piperazines; D017473:Receptors, Opioid, kappa; D014579:Urotensins; D013654:Taurine; D000077443:Acamprosate