Nonpeptide arginine vasopressin antagonists for both V1A and V2 receptors: synthesis and pharmacological properties of 4'-[5-(substituted methylidene)-2,3,4,5-tetrahydro-1H-1-ben zoazepine-1-carbonyl]benzanilide and 4'-[5-(substituted methyl)-2,3-dihydro-1H-1-benzoazepine-1- carbonyl]benzanilide derivatives.
Arginine vasopressin (AVP) has a dual action, i.e. vasoconstriction and water reabsorption via V1A and V2 receptors, and may play a role in a number of diseases, including congestive heart failure (CHF), hypertension, renal disease, edema, and hyponatremia. We have attempted to develop a new series of AVP antagonists for both V1A and V2 receptors based on the hypothesis that the blockade of both V1A and V2 receptors might be beneficial to CHF patients. In this report, a series of compounds structurally related to 4'-[5-(substituted methylidene)-2,3,4,5-tetrahydro-1H-1-benzoazepine-1-carbonyl ]benzanilide (exo-olefin isomer) and 4'-[5-(substituted methyl)-2,3-dihydro-1H-1-benzoazepine-1-carbonyl]benzanilide (endo-olefin isomer) were synthesized and examined to have AVP antagonist activity for both V1A and V2 receptors. As a result, it was found that the (E)-exo-olefin isomers showed more potent binding affinity compared with endo-olefin isomers. Among these (E)-exo-olefin isomers, (E)-N-methyl-{1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahyd ro-1H-1 -benzoazepin-5-ylidene}acetamide (14) exhibited the most potent binding affinity and (E)-N-methyl-(1-{4-[2-(4-methylphenyl)benzoylamino]benzoyl}-2,3,4,5- tetrahydro-1H-1-benzoazepin-5-ylidene)acetamide (20) exhibited a high AVP antagonist activity for both V1A and V2 receptors after intravenous administration. Details of the synthesis and pharmacological properties of this series are presented.
Matsuhisa
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A
Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd., Ibaraki, Japan.
Kikuchi
K
K
Sakamoto
K
K
Yatsu
T
T
Tanaka
A
A
D000818:Animals; D065092:Antidiuretic Hormone Receptor Antagonists; D001127:Arginine Vasopressin / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D001549:Benzamides / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D001552:Benzazepines / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D003655:Decerebrate State; D066298:In Vitro Techniques; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D011817:Rabbits; D051381:Rats; D013329:Structure-Activity Relationship
D065092:Antidiuretic Hormone Receptor Antagonists; D001549:Benzamides; D001552:Benzazepines; C119777:N-methyl-(1-(4-(2-(4-methylphenyl)benzoylamino)benzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepin-5-ylidene)acetamide; C119776:N-methyl-(1-(4-(2-methylbenzoylamino)benzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepin-5-ylidene)acetamide; D001127:Arginine Vasopressin