Synthesis and biological evaluation of novel chiral diazepine derivatives as bombesin receptor subtype-3 (BRS-3) agonists incorporating an antedrug approach

被引：17

作者：

Matsufuji, Tetsuyoshi ^{[1
]}

Shimada, Kousei ^{[1
]}

Kobayashi, Shozo ^{[1
]}

Ichikawa, Masanori ^{[1
]}

Kawamura, Asuka ^{[1
]}

Fujimoto, Teppei ^{[1
]}

Arita, Tsuyoshi ^{[1
]}

Hara, Takashi ^{[2
]}

Konishi, Masahiro ^{[2
]}

Abe-Ohya, Rie ^{[2
]}

Izumi, Masanori ^{[2
]}

Sogawa, Yoshitaka ^{[2
]}

Nagai, Yoko ^{[3
]}

Yoshida, Kazuhiro ^{[3
]}

Abe, Yasuyuki ^{[4
]}

Kimura, Takako ^{[5
]}

Takahashi, Hisashi ^{[1
]}

机构：

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

[2] Daiichi Sankyo Co Ltd, Cardiovasc Metabol Res Labs, Shinagawa Ku, Tokyo 1408710, Japan

[3] Daiichi Sankyo Co Ltd, Drug Metab & Pharmacokinet Res Labs, Shinagawa Ku, Tokyo 1408710, Japan

[4] Daiichi Sankyo Co Ltd, Med Safety Res Labs, Edogawa Ku, Tokyo 1348630, Japan

[5] Daiichi Sankyo RD NOVARE Co Ltd, Drug Discovery & Biomed Technol Unit, Edogawa Ku, Tokyo 1348630, Japan

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2015年 / 23卷 / 01期

关键词：

Anti-obesity; Antedrug; Bombesin receptor subtype-3 (BRS-3); Brain penetration; Diazepine; TERT-BUTANESULFINYL IMINES; ASYMMETRIC-SYNTHESIS; BODY-TEMPERATURE; NERVOUS-SYSTEM; OBESE SUBJECTS; WEIGHT-LOSS; DISCOVERY; OVERWEIGHT; AMINES; SIBUTRAMINE;

D O I：

10.1016/j.bmc.2014.11.018

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：

Novel compounds based on the lead BRS-3 agonists from our HTS compounds 2a and 2b have been synthesized with the focus on obtaining peripheral BRS-3 agonists. To identify potent anti-obesity compounds without adverse effects on the central nerve system, a labile carboxylic ester with an antedrug functionality was introduced onto the terminal position. Through the extensive synthetic exploration and the pharmacokinetic studies of oral administration in mice, the phenol ester 17c was selected due to the most suitable pharmacological profile. In the evaluation of food intake suppression in B6 mice, 17c showed significant in vivo efficacy and no clear adverse effect on heart rate and blood pressure change in dog iv infusion. Our study paved the way for development of anti-diabetes and obesity drugs with a safer profile. (C) 2014 Elsevier Ltd. All rights reserved.

引用

页码：89 / 104

页数：16

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