title: Aminomethylpiperazines as selective urotensin antagonists.
abstract: 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.
authors.affiliation: 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
authors.forename: Mark A
authors.initials: MA
authors.lastname: Hilfiker
authors.forename: Daohua
authors.initials: D
authors.lastname: Zhang
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Dowdell
authors.forename: Krista B
authors.initials: KB
authors.lastname: Goodman
authors.forename: John J
authors.initials: JJ
authors.lastname: McAtee
authors.forename: Jason W
authors.initials: JW
authors.lastname: Dodson
authors.forename: Andrew Q
authors.initials: AQ
authors.lastname: Viet
authors.forename: Gren Z
authors.initials: GZ
authors.lastname: Wang
authors.forename: Clark A
authors.initials: CA
authors.lastname: Sehon
authors.forename: David J
authors.initials: DJ
authors.lastname: Behm
authors.forename: Zining
authors.initials: Z
authors.lastname: Wu
authors.forename: Luz H
authors.initials: LH
authors.lastname: Carballo
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Douglas
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Neeb
mesh_terms: 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*
chemical_list: D010879:Piperazines; D017473:Receptors, Opioid, kappa; D014579:Urotensins; D013654:Taurine; D000077443:Acamprosate