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.
Subject(s)
Antidiuretic Hormone Receptor Antagonists , Benzazepines/chemistry , Spiro Compounds/chemistry , Animals , Antihypertensive Agents/administration & dosage , Antihypertensive Agents/chemistry , Antihypertensive Agents/metabolism , Antihypertensive Agents/pharmacokinetics , Benzazepines/administration & dosage , Benzazepines/pharmacokinetics , Benzazepines/pharmacology , Drug Evaluation, Preclinical , Female , Humans , Male , Rats , Rats, Long-Evans , Receptors, Vasopressin/metabolism , Receptors, Vasopressin/physiology , Spiro Compounds/administration & dosage , Spiro Compounds/metabolism , Spiro Compounds/pharmacokinetics , Spiro Compounds/pharmacology , Vasopressins/metabolismABSTRACT
A series of substituted spirobenzazepines was prepared and evaluated as V(1a) and V(2) dual vasopressin receptor antagonists. Compounds 7p and 7q have been shown to be not only potent inhibitors of vasopressin receptors, but also have exhibited an excellent overall pharmaceutical suitability profile.
Subject(s)
Antidiuretic Hormone Receptor Antagonists , Benzazepines/chemical synthesis , Animals , Benzazepines/metabolism , Benzazepines/pharmacology , Cell Line , Drug Evaluation, Preclinical/methods , Humans , Rats , Receptors, Vasopressin/metabolismABSTRACT
A novel series of spirobenzazepines was synthesized and evaluated for V1a and V2 receptor antagonist activity. Compounds 8b, 8i, and 8k have shown selective V1a receptor antagonist activity. Compounds 8p and 8q were shown to be dual V1a/V2 receptor antagonists.
