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.
Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd., Tsukuba, Ibaraki, Japan. shimada@yamanouchi.co.jp
Yoshiaki
Y
Shimada
Hiroaki
H
Akane
Nobuaki
N
Taniguchi
Akira
A
Matsuhisa
Noriyuki
N
Kawano
Kazumi
K
Kikuchi
Takeyuki
T
Yatsu
Atsuo
A
Tahara
Yuichi
Y
Tomura
Toshiyuki
T
Kusayama
Koh-ichi
K
Wada
Junko
J
Tsukada
Takashi
T
Tsunoda
Akihiro
A
Tanaka
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