Preparation of highly potent and selective non-peptide antagonists of the arginine vasopressin V1A receptor by introduction of a 2-ethyl-1H-1-imidazolyl group.
To find a new series of arginine vasopressin (AVP) V1A receptor antagonists, the influence of the 2-phenyl group of 2-phenyl-4'-[(2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)carbonyl]benzanilide (7) was investigated. Replacement of the 2-phenyl group by a 2-ethyl-1H-imidazol-1-yl group was effective in yielding a V1A-selective compound. Moreover, this imidazolyl group was introduced in the same position in YM-35471 (6), and further studies of these compounds were performed. Consequently, we found that the (Z)-4'-({4,4-difluoro-5-[(N-cyclopropylcarbamoyl)methylene]-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl}carbonyl)-2-(2-ethyl-1H-1-imidazol-1-yl)benzanilide (9f) exhibited highly potent affinity and selectivity, and was the most potent antagonist for the V1A receptor among our compounds. The synthesis and pharmacological evaluation of these compounds are described in this paper.
Shimada
Yoshiaki
Y
Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd., Tsukuba, Ibaraki, Japan. shimada@yamanouchi.co.jp
Akane
Hiroaki
H
Taniguchi
Nobuaki
N
Matsuhisa
Akira
A
Kawano
Noriyuki
N
Kikuchi
Kazumi
K
Yatsu
Takeyuki
T
Tahara
Atsuo
A
Tomura
Yuichi
Y
Kusayama
Toshiyuki
T
Wada
Koh-ichi
K
Tsukada
Junko
J
Tsunoda
Takashi
T
Tanaka
Akihiro
A
D065092:Antidiuretic Hormone Receptor Antagonists; D001127:Arginine Vasopressin / Q000378:metabolism; D007093:Imidazoles / Q000737:chemistry / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D017483:Receptors, Vasopressin / Q000378:metabolism; D016339:Spectrometry, Mass, Fast Atom Bombardment
D065092:Antidiuretic Hormone Receptor Antagonists; D007093:Imidazoles; D017483:Receptors, Vasopressin; D001127:Arginine Vasopressin