Chem. Pharm. Bull.

Chem. Pharm. Bull., 53(7),764-769, July 2005

Regular Articles

Preparation of Highly Potent and Selective Non-Peptide Antagonists of the Arginine Vasopressin V_1A Receptor by Introduction of a 2-Ethyl-1H-1-imidazolyl Group

Yoshiaki SHIMADA,^*^,a Hiroaki AKANE,^b Nobuaki TANIGUCHI,^a Akira MATSUHISA,^a Noriyuki KAWANO,^a Kazumi KIKUCHI,^a Takeyuki YATSU,^a Atsuo TAHARA,^a Yuichi TOMURA,^a Toshiyuki KUSAYAMA,^a Koh-ichi WADA,^a Junko TSUKADA,^b Takashi TSUNODA,^c and Akihiro TANAKA^d

^a Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd.; 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan: ^b Clinical Development Department, Yamanouchi Pharmaceutical Co., Ltd.; 3-17-1 Hasune, Itabashi-ku, Tokyo 174-8612, Japan: ^c Chemical Technology Laboratory, Yamanouchi Pharmaceutical Co., Ltd.; 160-2 Akahama, Takahagi, Ibaraki 318-0001, Japan: and ^d Corporate Communications Department, Yamanouchi Pharmaceutical Co., Ltd.; 2-3-11 Nihonbashi-honcho, Chuo-ku, Tokyo 103-8411, Japan. * To whom correspondence should be addressed. e-mail: shimada@yamanouchi.co.jp

To find a new series of arginine vasopressin (AVP) V_1A 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 V_1A-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 V_1A receptor among our compounds. The synthesis and pharmacological evaluation of these compounds are described in this paper

Key words arginine vasopressin; V_1A receptor selective antagonist; 2-ethyl-1H-1-imidazole

Regular Articles

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

Yoshiaki SHIMADA,*,a Hiroaki AKANE,b Nobuaki TANIGUCHI,a Akira MATSUHISA,a Noriyuki KAWANO,a Kazumi KIKUCHI,a Takeyuki YATSU,a Atsuo TAHARA,a Yuichi TOMURA,a Toshiyuki KUSAYAMA,a Koh-ichi WADA,a Junko TSUKADA,b Takashi TSUNODA,c and Akihiro TANAKAd

Preparation of Highly Potent and Selective Non-Peptide Antagonists of the Arginine Vasopressin V_1A Receptor by Introduction of a 2-Ethyl-1H-1-imidazolyl Group

Yoshiaki SHIMADA,^*^,a Hiroaki AKANE,^b Nobuaki TANIGUCHI,^a Akira MATSUHISA,^a Noriyuki KAWANO,^a Kazumi KIKUCHI,^a Takeyuki YATSU,^a Atsuo TAHARA,^a Yuichi TOMURA,^a Toshiyuki KUSAYAMA,^a Koh-ichi WADA,^a Junko TSUKADA,^b Takashi TSUNODA,^c and Akihiro TANAKA^d