Preparation of non-peptide, highly potent and selective antagonists of arginine vasopressin V1A receptor by introduction of alkoxy groups.
A series of compounds structurally related to 4'-[(4,4-difluoro-5-methylidene-2,3,4,5-tetrahydro-1H-1-benzoazepin-1-yl)carbonyl]benzanilide were synthesized and evaluated for arginine vasopressin (AVP) antagonistic activity. Compounds with alkoxy groups (especially ethoxy group) at the 2'-position of benzanilide possessed potent affinity and selectivity for the V1A receptor versus V2 receptor. Further study has shown that the introduction of 4,4-dimethylaminopiperidino and morpholino groups at carbonylmethylene exhibited more potent affinity and selectivity for V1A receptors. Consequently, we found that the (Z)-4'-([4,4-Difluoro-5-[(4-dimethylaminopiperidino)carbonylmethylene]-2,3,4,5-tetrahydro-1H-1-benzoazepin-1-yl]carbonyl)-2-ethoxybenzanilide monohydrochloride (8d) and the (Z)-4'-[(4,4-Difluoro-5-morpholinocarbamoylethylene-2,3,4,5-tetrahydro-1H-1-benzoazepin-1-yl)carbonyl]-2-ethoxybenzanilide (8q) exhibited potent and selective V1A receptor antagonist activity. The synthesis and pharmacological properties of these compounds are detailed in this paper.
Shimada
Yoshiaki
Y
Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd., Tsukuba, Ibaraki, Japan. shimada@yamanouchi.co.jp
Taniguchi
Nobuaki
N
Matsuhisa
Akira
A
Yatsu
Takeyuki
T
Tahara
Atsuo
A
Tanaka
Akihiro
A
D019342:Acetic Acid / Q000737:chemistry; D000813:Anilides / Q000138:chemical synthesis* / Q000494:pharmacology*; D000818:Animals; D065092:Antidiuretic Hormone Receptor Antagonists; D001127:Arginine Vasopressin / Q000037:antagonists & inhibitors*; D001381:Azepines / Q000138:chemical synthesis* / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D016466:CHO Cells; D002462:Cell Membrane / Q000378:metabolism; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D006224:Cricetinae; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007202:Indicators and Reagents; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D051381:Rats; D013329:Structure-Activity Relationship
C483333:4'-((4,4-difluoro-5-methylidene-2,3,4,5-tetrahydro-1H-1-benzoazepin-1-yl)carbonyl)benzanilide; D000813:Anilides; D065092:Antidiuretic Hormone Receptor Antagonists; D001381:Azepines; D007202:Indicators and Reagents; D001127:Arginine Vasopressin; D019342:Acetic Acid