Novel Indole-N-glucoside, TA-1887 As a Sodium Glucose Cotransporter 2 Inhibitor for Treatment of Type 2 Diabetes
†Medicinal Chemistry Research Laboratories, ‡Pharmacology Research Laboratories, and §DMPK Research Laboratories, Mitsubishi Tanabe Pharma Corporation, 2-2-50 Kawagishi, Toda, Saitama 335-8505, Japan
ACS Med. Chem. Lett., 2014, 5 (1), pp 51–55
DOI: 10.1021/ml400339b
Publication Date (Web): November 13, 2013
Copyright © 2013 American Chemical Society
Abstract
Inhibition of the renal sodium glucose cotransporter (SGLT) increases urinary glucose excretion (UGE) and thus reduces blood glucose levels during hyperglycemia. To explore the potential of new antihyperglycemic agents, we synthesized and determined the human SGLT2 (hSGLT2) inhibitory potential of novel substituted 3-benzylindole-N-glucosides 6. Optimization of 6 resulted in the discovery of 3-(4-cyclopropylbenzyl)-4-fluoroindole-N-glucoside 6a-4 (TA-1887), a highly potent and selective hSGLT2 inhibitor, with pronounced antihyperglycemic effects in high-fat diet-fed KK (HF-KK) mice. Our results suggest the potential of indole-N-glucosides as novel antihyperglycemic agents through inhibition of renal SGLT2.
Description of in vitro hSGLT1, hSGLT2, and GLUT1 assays and in vivo urinary glucose excretion and blood glucose-lowering studies; detailed synthetic procedure for 6a-1, 6a-2, 6a-3, 6b-1, 6b-4, 6c-4, 6a-4, 6c-5, 6c-6, and 6a-6; HPLC analysis of 6a-4. This material is available free of charge via the Internet at http://pubs.acs.org.
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