The incidence of type 2 diabetes is markedly increasing in western countries and some developing countries, leading to a strong demand for novel drugs with improved efficacy and safety. Plasma glucose is filtered and reabsorbed in the kidney via sodium glucose co-transporter 2 (SGLT2). In a previous study, the natural phenol-O-glucoside product phlorizin was optimized to the first orally active SGLT2 inhibitor. The resulting compound T-1095 enhances urinary glucose excretion and lowers blood glucose levels independent of the action of insulin. We recently demonstrated that the aryl-C-glucoside canagliflozin is a metabolically stable SGLT2 inhibitor with excellent in vivo potency, and it has been launched in the USA. Further investigations of the potential of a series of glucosides demonstrated SGLT2 inhibitory activity of novel aniline- and heteroaromatic-N-glucosides. Through optimization of these compounds, we identified 3-(4-cyclopropylbenzyl)-4-fluoroindole-N-glucoside (TA-1887), as a highly potent and selective SGLT2 inhibitor. Oral administration of TA-1887 exerted pronounced antihyperglycemic effects in high-fat diet-fed KK (HF-KK) mice. Analysis of the structure�activity relationships revealed the potential of indole-N-glucosides as antihyperglycemic agents that inhibit renal SGLT2.

Discovery of the novel indole-<i>N</i>-glucoside TA-1887 as a sodium glucose co-transporter 2 inhibitor

248th National Meeting (2014)

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Discovery of the novel indole-N-glucoside TA-1887 as a sodium glucose co-transporter 2 inhibitor