title: Nonpeptide urotensin-II receptor antagonists: a new ligand class based on piperazino-phthalimide and piperazino-isoindolinone subunits.
abstract: We have discovered two related chemical series of nonpeptide urotensin-II (U-II) receptor antagonists based on piperazino-phthalimide (5 and 6) and piperazino-isoindolinone (7) scaffolds. These structure types are distinctive from those of U-II receptor antagonist series reported in the literature. Antagonist 7a exhibited single-digit nanomolar potency in rat and human cell-based functional assays, as well as strong binding to the human U-II receptor. In advanced pharmacological testing, 7a blocked the effects of U-II in vitro in a rat aortic ring assay and in vivo in a rat ear-flush model. A discussion of U-II receptor antagonist pharmacophores is presented, and a specifically defined model is suggested from tricycle 13, which has a high degree of conformational constraint.
authors.affiliation: Johnson & Johnson Pharmaceutical Research & Development, Welsh & McKean Roads, Spring House, Pennsylvania 19477-0776, USA.
authors.forename: Edward C
authors.initials: EC
authors.lastname: Lawson
authors.forename: Diane K
authors.initials: DK
authors.lastname: Luci
authors.forename: Shyamali
authors.initials: S
authors.lastname: Ghosh
authors.forename: William A
authors.initials: WA
authors.lastname: Kinney
authors.forename: Charles H
authors.initials: CH
authors.lastname: Reynolds
authors.forename: Jenson
authors.initials: J
authors.lastname: Qi
authors.forename: Charles E
authors.initials: CE
authors.lastname: Smith
authors.forename: Yuanping
authors.initials: Y
authors.lastname: Wang
authors.forename: Lisa K
authors.initials: LK
authors.lastname: Minor
authors.forename: Barbara J
authors.initials: BJ
authors.lastname: Haertlein
authors.forename: Tom J
authors.initials: TJ
authors.lastname: Parry
authors.forename: Bruce P
authors.initials: BP
authors.lastname: Damiano
authors.forename: Bruce E
authors.initials: BE
authors.lastname: Maryanoff
mesh_terms: D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000502:physiology; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D057166:High-Throughput Screening Assays; D006801:Humans; D054833:Isoindoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D008297:Male; D010797:Phthalimides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D000077489:Piperazine; D010879:Piperazines / Q000737:chemistry*; D051381:Rats; D017208:Rats, Wistar; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors*
chemical_list: D054833:Isoindoles; D010797:Phthalimides; D010879:Piperazines; D043562:Receptors, G-Protein-Coupled; C121697:UTS2R protein, human; C473142:Uts2r protein, rat; C037431:phthalimide; D000077489:Piperazine