Design, synthesis and biological evaluation of (2S, 3R, 4R, 5S, 6R)-5-fluoro-6-(hydroxymethyl)-2-aryltetrahydro-2H-pyran-3,4-diols as potent and orally active SGLT dual inhibitors

被引：10

作者：

Xu, Guozhang ^{[1
]}

Gaul, Michael D. ^{[1
]}

Kuo, Gee-Hong ^{[1
]}

Du, Fuyong ^{[1
]}

Xu, June Zhi ^{[1
]}

Wallace, Nathaniel ^{[1
]}

Hinke, Simon ^{[1
]}

Kirchner, Thomas ^{[1
]}

Silva, Jose ^{[1
]}

Huebert, Norman D. ^{[1
]}

Lee, Seunghun ^{[1
]}

Murray, William ^{[1
]}

Liang, Yin ^{[1
]}

Demarest, Keith ^{[1
]}

机构：

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

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2018年 / 28卷 / 21期

关键词：

Diabetes; Glucose transporter; SGLT1; inhibitor; SGLT2; Bioisostere; C-Aryl glucoside; AFFINITY NA+/GLUCOSE COTRANSPORTER; C-GLUCOSIDE; DISCOVERY; TRANSPORT; KIDNEY;

D O I：

10.1016/j.bmcl.2018.09.025

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A new series of (2S, 3R, 4R, 5S, 6R)-5-fluoro-6-(hydroxymethyl)-2-aryltetrahydro-2H-pyran-3,4-diols as dual inhibitors of sodium glucose co-transporter proteins (SGLTs) were disclosed. Two methods were developed to efficiently synthesize C-5-fluoro-lactones 3 and 4, which are key intermediates to the C-5-fluoro-hexose based C-aryl glucosides. Compound 2b demonstrated potent hSGLT1 and hSGLT2 inhibition (IC50 = 43 nM for SGLT1 and IC50 = 9 nM for SGLT2). It showed robust inhibition of blood glucose excursion in oral glucose tolerance test (OGTT) in Sprague Dawley (SD) rats and exerted pronounced antihyperglycemic effects in db/db mice and high-fat diet-fed ZDF rats when dosed orally at 10 mg/kg.

引用

页码：3446 / 3453

页数：8

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