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

  • J Med Chem. 2017 May 25;60(10):4173-4184. doi: 10.1021/acs.jmedchem.6b01818.
Yao Li  1 ,  Zongjun Shi  1 ,  Lei Chen  1 ,  Suxin Zheng  1 ,  Sheng Li  1 ,  Bo Xu  1 ,  Zhenhong Liu  1 ,  Jianyu Liu  1 ,  Chongyang Deng  1 ,  Fei Ye  1
Affiliations
  • 1. Haisco Pharmaceuticals Group Co. Ltd. , 136 Baili Road, Wenjiang District, Chengdu 611130, China.
PMID: 28447791 DOI: 10.1021/acs.jmedchem.6b01818
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.

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