title: Nonpeptide arginine vasopressin antagonists for both V1A and V2 receptors: synthesis and pharmacological properties of 2-phenyl-4'-(2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-1-carbonyl) benzanilide derivatives.
abstract: A series of compounds structurally related to 2-phenyl-4'-(2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-1-carbonyl) benzanilide was synthesized and demonstrated to have arginine vasopressin (AVP) antagonist activity for both V1A and V2 receptors. The introduction of a hydrophilic substituent group into the 5-position of the benzodiazepine ring resulted in an increase in oral availability. Especially, the (3-pyridyl)methyl (31b), the 2-(4-methyl-1,4-diazepan-1-yl)-2-oxoethyl (32i), and the 2-(4-methylpiperazin-1-yl)ethyl (33g) derivatives exhibited high antagonist activities and high oral availability. Details of the synthesis and pharmacological properties of this series are presented.
authors.affiliation: Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd., Ibaraki, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Matsuhisa
authors.forename: H
authors.initials: H
authors.lastname: Koshio
authors.forename: K
authors.initials: K
authors.lastname: Sakamoto
authors.forename: N
authors.initials: N
authors.lastname: Taniguchi
authors.forename: T
authors.initials: T
authors.lastname: Yatsu
authors.forename: A
authors.initials: A
authors.lastname: Tanaka
mesh_terms: D000813:Anilides / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D065092:Antidiuretic Hormone Receptor Antagonists; D001127:Arginine Vasopressin / Q000037:antagonists & inhibitors*; D001682:Biological Availability; D005260:Female; D066298:In Vitro Techniques; D007211:Indoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D009682:Magnetic Resonance Spectroscopy; D011759:Pyrrolidines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011817:Rabbits; D051381:Rats; D018045:Receptors, Oxytocin / Q000187:drug effects / Q000378:metabolism
chemical_list: D000813:Anilides; D065092:Antidiuretic Hormone Receptor Antagonists; D007211:Indoles; D011759:Pyrrolidines; D018045:Receptors, Oxytocin; D001127:Arginine Vasopressin; C082134:relcovaptan