Synthesis and biological evaluation of novel imidazol-1-ylacetic acid derivatives as non-brain penetrant bombesin receptor subtype-3 (BRS-3) agonists

被引：4

作者：

Kiyotsuka, Yohei ^{[1
]}

Shimada, Kousei ^{[1
]}

Kobayashi, Shozo ^{[1
]}

Suzuki, Masanori ^{[1
]}

Akiu, Mayuko ^{[1
]}

Asano, Masayoshi ^{[1
]}

Sogawa, Yoshitaka ^{[2
]}

Hara, Takashi ^{[2
]}

Konishi, Masahiro ^{[2
]}

Abe-Ohya, Rie ^{[2
]}

Izumi, Masanori ^{[2
]}

Nagai, Yoko ^{[3
]}

Yoshida, Kazuhiro ^{[3
]}

Abe, Yasuyuki ^{[4
]}

Takamori, Hideo ^{[4
]}

Takahashi, Hisashi ^{[1
]}

机构：

[1] Daiichi Sankyo Co Ltd, Med Chem Res Labs, Shinagawa Ku, 1-2-58 Hiromachi, Tokyo 1408710, Japan

[2] Daiichi Sankyo Co Ltd, Cardiovasc Metab Res Labs, Shinagawa Ku, 1-2-58 Hiromachi, Tokyo 1408710, Japan

[3] Daiichi Sankyo Co Ltd, Drug Metab & Pharmacokinet Res Labs, Shinagawa Ku, 1-2-58 Hiromachi, Tokyo 1408710, Japan

[4] Daiichi Sankyo Co Ltd, Med Safety Res Labs, Edogawa Ku, 1-16-13 Kitakasai, Tokyo 1348630, Japan

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2016年 / 26卷 / 17期

关键词：

Anti-obesity; Antedrug; Bombesin receptor subtype-3 (BRS-3); Brain penetration; Imidazole; MK-5046; OBESITY; POTENT; DISCOVERY; RAT;

D O I：

10.1016/j.bmcl.2016.07.056

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Novel compounds based on la were synthesized with the focus of obtaining agonists acting upon peripheral BRS-3. To identify potent anti-obesity compounds without adverse effects on the central nervous system (CNS), a carboxylic acid moiety and a labile carboxylic ester with an antedrug functionality were introduced. Through the extensive synthetic exploration and the pharmacokinetic studies of intravenous administration in mice, the ester 2b was selected owing to its most suitable pharmacological profile. In the evaluation of food intake suppression in C57BL/6N mice, 2b showed significant in vivo efficacy and no clear adverse effects on blood pressure change in dogs administered the compound by intravenous infusion. (C) 2016 Elsevier Ltd. All rights reserved.

引用

页码：4205 / 4210

页数：6

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