Next-generation spirobenzazepines: identification of RWJ-676070 as a balanced vasopressin V1a/V2 receptor antagonist for human clinical studies.
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.
Xiang
Min Amy
MA
Research and Early Development, Johnson & Johnson Pharmaceutical Research & Development, 8 Clarke Drive, Cranbury, NJ 08512, USA.
Rybczynski
Philip J
PJ
Patel
Mona
M
Chen
Robert H
RH
McComsey
David F
DF
Zhang
Han-Cheng
HC
Gunnet
Joseph W
JW
Look
Richard
R
Wang
Yuanping
Y
Minor
Lisa K
LK
Zhong
H Marlon
HM
Villani
Frank J
FJ
Demarest
Keith T
KT
Damiano
Bruce P
BP
Maryanoff
Bruce E
BE
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
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