Discovery of pyridone-containing imidazolines as potent and selective inhibitors of neuropeptide Y Y5 receptor

被引：17

作者：

Ando, Makoto ^{[1
]}

Sato, Nagaaki ^{[1
]}

Nagase, Tsuyoshi ^{[1
]}

Nagai, Keita ^{[1
]}

Ishikawa, Shiho ^{[1
]}

Takahashi, Hirobumi ^{[1
]}

Ohtake, Norikazu ^{[1
]}

Ito, Junko ^{[1
]}

Hirayama, Mioko ^{[1
]}

Mitobe, Yuko ^{[1
]}

Iwaasa, Hisashi ^{[1
]}

Gomori, Akira ^{[1
]}

Matsushita, Hiroko ^{[1
]}

Tadano, Kiyoshi ^{[1
]}

Fujino, Naoko ^{[1
]}

Tanaka, Sachiko ^{[1
]}

Ohe, Tomoyuki ^{[1
]}

Ishihara, Akane ^{[1
]}

Kanatani, Akio ^{[1
]}

Fukami, Takehiro ^{[1
]}

机构：

[1] Banyu Pharmaceut Co Ltd, Merck Res Labs, Tsukuba Res Inst, Tsukuba, Ibaraki 3002611, Japan

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2009年 / 17卷 / 16期

关键词：

Neuropeptide Y Y5 receptor; Anti-obesity; Y5; antagonist; Imidazoline class; INCREASED HYPOTHALAMIC CONTENT; MESSENGER-RIBONUCLEIC-ACID; OBESITY SYNDROME; MICE; ANTAGONISTS; EXPRESSION; DEFICIENT; EFFICIENT; NUCLEUS; RATS;

D O I：

10.1016/j.bmc.2009.05.069

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

A series of 2-pyridone-containing imidazoline derivatives was synthesized and evaluated as neuropeptide Y Y5 receptor antagonists. Optimization of the 2-pyridone structure on the 2-position of the imidazoline ring led to identification of 1-(difluoromethyl)-5-[(4S,5S)-4-(4-fluorophenyl)-4-(6-fluoropyridin- 3-yl)-5-methyl-4,5-dihydro-1H-imidazol-2-yl] pyridin-2(1H)-one (7m). Compound 7m displayed statistically significant inhibition of food intake in an agonist-induced food intake model in SD rats and no adverse cardiovascular effects in anesthetized dogs. In addition, markedly higher brain penetrability and a lower plasma Occ90 value were observed in P-gp-deficient mdr1a (-/-) mice compared to mdr1a (+/+) mice after oral administration of 7m. (C) 2009 Elsevier Ltd. All rights reserved.

引用

页码：6106 / 6122

页数：17

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