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-y l)carbonyl]-2-phenylbenzanilide derivatives.
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.
Shimada
Y
Y
Institute for Drug Discovery Research, Yamanouchi Pharmaceultical Co, Ltd, Tsukuba-shi, Ibaraki, Japan. shimada@yamanouchi.co.jp
Taniguchi
N
N
Matsuhisa
A
A
Sakamoto
K
K
Yatsu
T
T
Tanaka
A
A
D000813:Anilides / Q000138:chemical synthesis*; D000818:Animals; D065092:Antidiuretic Hormone Receptor Antagonists; D001127:Arginine Vasopressin / Q000037:antagonists & inhibitors*; D001381:Azepines / Q000138:chemical synthesis*; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D066298:In Vitro Techniques; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008566:Membranes; D051381:Rats; D013329:Structure-Activity Relationship
D000813:Anilides; D065092:Antidiuretic Hormone Receptor Antagonists; D001381:Azepines; D001127:Arginine Vasopressin