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Identification of an oxime-containing C-glucosylarene as a potential inhibitor of sodium-dependent glucose co-transporter 2.

Abstract：

:Treatment of hyperglycemia with drugs that block renal glucose reabsorption via inhibition of sodium-dependent glucose cotransporter 2 (SGLT2) is a novel approach to diabetes management. In this study, twenty-seven aryl C-glycosides bearing a C=N/C-N linkage at the glucosyl C6 position were designed, synthesized and evaluated for their inhibitory activity against human SGLT2 (hSGLT2). Compounds with good hSGLT2 inhibition were further investigated to determine their selectivity over hSGLT1. Of these, five representative aryl C-glycosides were chosen for pharmacokinetic analysis. Oxime 2a was determined to have the most promising pharmacokinetic properties and was selected for in vivo glucosuria and plasma glucose level studies, which found it to exhibit comparable efficacy to dapagliflozin (1). Furthermore, 2a was not found to exhibit either significant cytotoxicity (CC50 > 50 μM) or human ether-a-go-go related gene (hERG) inhibition (2% inhibition at 10 μM). Taken together, these efforts culminated in the discovery of oxime 2a as a potential SGLT2 inhibitor.

journal_name

Eur J Med Chem

journal_title

European journal of medicinal chemistry

authors

Yuan MC,Yeh TK,Chen CT,Song JS,Huang YC,Hsieh TC,Huang CY,Huang YL,Wang MH,Wu SH,Yao CH,Chao YS,Lee JC

doi

10.1016/j.ejmech.2017.11.019

subject

Has Abstract

pub_date

2018-01-01 00:00:00

pages

611-620

eissn

0223-5234

issn

1768-3254

pii

S0223-5234(17)30914-5

journal_volume

143

pub_type

杂志文章

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