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标题：Synthesis and Structure–Activity Relationship of C-Phenyl D-Glucitol (TP0454614) Derivatives as Selective Sodium-Dependent Glucose Cotransporter 1 (SGLT1) Inhibitors
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作者：Shoichi Kuroda ; Yohei Kobashi ; Madoka Kawamura 等
期刊名称：Chemical and Pharmaceutical Bulletin
印刷版ISSN：0009-2363
电子版ISSN：1347-5223
出版年度：2020
卷号：68
期号：7
页码：635-652
DOI：10.1248/cpb.c20-00089
出版社：The Pharmaceutical Society of Japan
摘要：Sodium-glucose cotransporter 1 (SGLT1) is the primary transporter for glucose absorption from the gastrointestinal tract. While C -phenyl D-glucitol derivative SGL5213 has been reported to be a potent intestinal SGLT1 inhibitor for use in the treatment of type 2 diabetes, no SGLT1 selectivity was found in vitro (IC50 29 nM for hSGLT1 and 20 nM for hSGLT2). In this study we found a new method of synthesizing key intermediates 12 by a one-pot three-component condensation reaction and discovered C -phenyl D-glucitol 41j (TP0454614), which has >40-fold SGLT1 selectivity in vitro (IC50 26 nM for hSGLT1 and 1101 nM for hSGLT2). The results of our study have provided new insights into the structure–activity relationships (SARs) of the SGLT1 selectivity of C -glucitol derivatives.
关键词：sodium-dependent glucose cotransporter 1;heart failure;type 2 diabetes;sodium-dependent glucose cotransporter 2;selective sodium-dependent glucose cotransporter 1 inhibitor;C-phenyl D-glucitol derivative