Synthesis and biological evaluation of benzocyclobutane-C-glycosides as potent and orally active SGLT1/SGLT2 dual inhibitors

被引：32

作者：

Kuo, Gee-Hong ^{[1
]}

Gaul, Micheal D. ^{[1
]}

Liang, Yin ^{[1
]}

Xu, June Z. ^{[1
]}

Du, Fuyong ^{[1
]}

Hornby, Pamela ^{[1
]}

Xu, Guozhang ^{[1
]}

Qi, Jenson ^{[1
]}

Wallace, Nathaniel ^{[1
]}

Lee, Seunghun ^{[1
]}

Grant, Eugene ^{[1
]}

Murray, William V. ^{[1
]}

Demarest, Keith ^{[1
]}

机构：

[1] Janssen Res & Dev LLC, Cardiovasc & Metab Res, Welsh & McKean Rd, Spring House, PA 19477 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2018年 / 28卷 / 07期

关键词：

Benzocyclobutane-C-glycosides; SGLT1/2 dual inhibitor; Anti-hyperglycemic effect; SGLT2; INHIBITORS; DESIGN; GLUCOSIDE;

D O I：

10.1016/j.bmcl.2018.02.057

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Synthesis and biological evaluation of benzocyclobutane-C-glycosides as potent and orally active SGLT1/SGLT2 dual inhibitors are described. Compound 19 showed high inhibitory potency at SGLT1 (IC50 = 45 nM), and excellent potency at SGLT2 (IC50 = 1 nM). It also displayed excellent PK profiles in mice, rats, dogs and monkeys (F = 78-107%). In SD rats, compound 19 treatments significantly reduced blood glucose levels in a dose-dependent manner. In ZDF rats, compound 19 displayed anti-hyperglycemic effect up to 24 h. Therefore, compound 19 may serve as valuable pharmacological tool, and potential use as a treatment for metabolic syndrome. (C) 2018 Elsevier Ltd. All rights reserved.

引用

页码：1182 / 1187

页数：6

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