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Highly Potent and Orally Active Non-Peptide Arginine Vasopressin Antagonists for Both V1A and V2 Receptors: Synthesis and Pharmacological Properties of 4'-[(4,4-Difluoro-5-methylidene-2,3,4,5-tetrahydro-1H-1-benzoazepin-1-yl)carbonyl]-2-phenylbenzanililde Derivatives.
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2000
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Potent AffinityOrganic ChemistryPharmacotherapyPharmaceutical ChemistryV2 ReceptorsMedicinal ChemistryHighly PotentArginine VasopressinBiochemistryMechanism Of ActionPharmacological AgentNon-peptide LigandPharmacologyFunctional SelectivityNatural SciencesPhysiologyBoth V1aNeuropeptide ReceptorMedicineDrug DiscoveryNeuropeptides
A series of compounds structurally related to 4'-[(4,4-difluoro-5-methylidene-2,3,4,5-tetrahydro-1H-1-benzoaz epin-1-yl) carbonyl]-2-phenylbenzanilide were synthesized and evaluated for arginine vasopressin (AVP) antagonistic activity. Compounds with a (Z)-olefin geometry at the 5-position of benzoazepine possessed potent affinity for both the V1A and V2 receptors. Further study has shown that one of these derivatives, (Z)-4'-(¿4,4-difluoro-5-[(4-dimethylaminopiperidino)carbonylmet hylene]-2,3,4,5-tetrahydro-1H-1-benzoazepin-1-yI¿carbonyl)2- phenylbenzanilide monohydrochloride (29, YM-35471), exhibits exceptionally potent affinity for both of V1A and V2 receptors, even when administered orally. The synthesis and pharmacological properties of this compound are detailed in this paper.