发现一种用于治疗2型糖尿病的强效、选择性肾钠依赖性葡萄糖转运蛋白2（SGLT2）抑制剂（HSK0935）。

Discovery of a Potent, Selective Renal Sodium-Dependent Glucose Cotransporter 2 (SGLT2) Inhibitor (HSK0935) for the Treatment of Type 2 Diabetes.

作者信息

Li Yao, Shi Zongjun, Chen Lei, Zheng Suxin, Li Sheng, Xu Bo, Liu Zhenhong, Liu Jianyu, Deng Chongyang, Ye Fei

机构信息

Haisco Pharmaceuticals Group Co. Ltd. , 136 Baili Road, Wenjiang District, Chengdu 611130, China.

出版信息

J Med Chem. 2017 May 25;60(10):4173-4184. doi: 10.1021/acs.jmedchem.6b01818. Epub 2017 May 5.

DOI:10.1021/acs.jmedchem.6b01818

PMID:28447791

Abstract

A new class of potent and highly selective SGLT2 inhibitors is disclosed. Compound 31 (HSK0935) demonstrated excellent hSGLT2 inhibition of 1.3 nM and a high hSGLT1/hSGLT2 selectivity of 843-fold. It showed robust urinary glucose excretion in Sprague-Dawley (SD) rats and affected more urinary glucose excretion in Rhesus monkeys. Finally, an efficient synthetic route has been developed featuring a ring-closing cascade reaction to incorporate a double ketal 1-methoxy-6,8-dioxabicyclo[3.2.1]octane ring system.

摘要

公开了一类新型的强效且高选择性的SGLT2抑制剂。化合物31（HSK0935）表现出出色的hSGLT2抑制活性，IC50为1.3 nM，并且具有843倍的高hSGLT1/hSGLT2选择性。它在Sprague-Dawley（SD）大鼠中显示出强劲的尿糖排泄，并且在恒河猴中对尿糖排泄的影响更大。最后，开发了一种高效的合成路线，其特征在于通过闭环级联反应引入双缩酮1-甲氧基-6,8-二氧杂双环[3.2.1]辛烷环系统。