Bridged bicyclic vasopressin receptor antagonists with V(2)-selective or dual V(1a)/V(2) activity.
The synthesis and biological testing of a novel series of nonpeptide vasopressin receptor antagonists, containing a bridged bicyclic nucleus, are reported. Variation of substituents (R(1)-R(3)) in general formula 3, and the configuration of the stereocenter, resulted in potent V(2)-selective (e.g., 5) and balanced dual V(1a)/V(2) (e.g., 10) compounds. Data from receptor binding, cell-based functional, and in vivo assays are presented [corrected]
Dyatkin
Alexey B
AB
Drug Discovery, Johnson and Johnson Pharmaceutical Research and Development, Spring House, PA 19477-0776, USA.
Hoekstra
William J
WJ
Hlasta
Dennis J
DJ
Andrade-Gordon
Patricia
P
de Garavilla
Lawrence
L
Demarest
Keith T
KT
Gunnet
Joseph W
JW
Hageman
William
W
Look
Richard
R
Maryanoff
Bruce E
BE
D000818:Animals; D065092:Antidiuretic Hormone Receptor Antagonists; D000959:Antihypertensive Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D001127:Arginine Vasopressin / Q000037:antagonists & inhibitors / Q000494:pharmacology; D001569:Benzodiazepines / Q000138:chemical synthesis / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D001643:Bridged Bicyclo Compounds / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D002478:Cells, Cultured; D002851:Chromatography, High Pressure Liquid; D003404:Creatinine / Q000652:urine; D004573:Electrolytes / Q000652:urine; D006572:Heterocyclic Compounds, Bridged-Ring / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D006973:Hypertension / Q000139:chemically induced / Q000517:prevention & control; D008297:Male; D013058:Mass Spectrometry; D008968:Molecular Conformation; D009994:Osmolar Concentration; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000187:drug effects; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014563:Urodynamics / Q000187:drug effects
D065092:Antidiuretic Hormone Receptor Antagonists; D000959:Antihypertensive Agents; D001643:Bridged Bicyclo Compounds; D004573:Electrolytes; D006572:Heterocyclic Compounds, Bridged-Ring; D011994:Recombinant Proteins; D001127:Arginine Vasopressin; D001569:Benzodiazepines; D003404:Creatinine