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.
MeSH terms
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Animals
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Antidiuretic Hormone Receptor Antagonists*
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Antihypertensive Agents / administration & dosage
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Antihypertensive Agents / chemistry
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Antihypertensive Agents / metabolism
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Antihypertensive Agents / pharmacokinetics
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Benzazepines / administration & dosage
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Benzazepines / chemistry*
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Benzazepines / pharmacokinetics
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Benzazepines / pharmacology
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Drug Evaluation, Preclinical
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Female
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Humans
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Male
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Rats
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Rats, Long-Evans
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Receptors, Vasopressin / metabolism
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Receptors, Vasopressin / physiology
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Spiro Compounds / administration & dosage
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Spiro Compounds / chemistry*
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Spiro Compounds / metabolism
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Spiro Compounds / pharmacokinetics
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Spiro Compounds / pharmacology
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Vasopressins / metabolism
Substances
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Antidiuretic Hormone Receptor Antagonists
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Antihypertensive Agents
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Benzazepines
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JNJ-17158063
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RWJ-339489
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RWJ-676070
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Receptors, Vasopressin
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Spiro Compounds
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Vasopressins