title: Next-generation spirobenzazepines: identification of RWJ-676070 as a balanced vasopressin V1a/V2 receptor antagonist for human clinical studies.
abstract: We have continued to explore spirobenzazepines as vasopressin receptor antagonists to follow up on RWJ-339489 (2), which had advanced into preclinical development. Further structural modifications were pursued to find a suitable backup compound for human clinical studies. Thus, we identified carboxylic acid derivative 3 (RWJ-676070; JNJ-17158063) as a potent, balanced vasopressin V(1a)/V(2) receptor antagonist with favorable properties for clinical development. Compound 3 is currently undergoing human clinical investigation.
authors.affiliation: Research and Early Development, Johnson & Johnson Pharmaceutical Research & Development, 8 Clarke Drive, Cranbury, NJ 08512, USA.
authors.forename: Min Amy
authors.initials: MA
authors.lastname: Xiang
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Rybczynski
authors.forename: Mona
authors.initials: M
authors.lastname: Patel
authors.forename: Robert H
authors.initials: RH
authors.lastname: Chen
authors.forename: David F
authors.initials: DF
authors.lastname: McComsey
authors.forename: Han-Cheng
authors.initials: HC
authors.lastname: Zhang
authors.forename: Joseph W
authors.initials: JW
authors.lastname: Gunnet
authors.forename: Richard
authors.initials: R
authors.lastname: Look
authors.forename: Yuanping
authors.initials: Y
authors.lastname: Wang
authors.forename: Lisa K
authors.initials: LK
authors.lastname: Minor
authors.forename: H Marlon
authors.initials: HM
authors.lastname: Zhong
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Villani
authors.forename: Keith T
authors.initials: KT
authors.lastname: Demarest
authors.forename: Bruce P
authors.initials: BP
authors.lastname: Damiano
authors.forename: Bruce E
authors.initials: BE
authors.lastname: Maryanoff
mesh_terms: D000818:Animals; D065092:Antidiuretic Hormone Receptor Antagonists; D000959:Antihypertensive Agents / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics; D001552:Benzazepines / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical; D005260:Female; D006801:Humans; D008297:Male; D051381:Rats; D020318:Rats, Long-Evans; D017483:Receptors, Vasopressin / Q000378:metabolism / Q000502:physiology; D013141:Spiro Compounds / Q000008:administration & dosage / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology; D014667:Vasopressins / Q000378:metabolism
chemical_list: D065092:Antidiuretic Hormone Receptor Antagonists; D000959:Antihypertensive Agents; D001552:Benzazepines; C526852:JNJ-17158063; C526851:RWJ-339489; C526925:RWJ-676070; D017483:Receptors, Vasopressin; D013141:Spiro Compounds; D014667:Vasopressins