Exploration of novel C-glucoside formation and application for SGLT2 inhibitors - Discovery of canagliflozin as a SGL T2 inhibitor

Shigeki Sakamaki, Eiji Kawanishi, Sumihiro Nomura

Research output: Contribution to journalReview articlepeer-review

1 Citation (Scopus)

Abstract

Inhibition of sodium glucose co-transporter 2 (SGLT2) in vivo increases urinary glucose excretion (UGE) and controls blood glucose levels in hyperglycemic animals. T-1095 is the first orally active SGLT2 inhibitor, and it was discovered by optimizing the natural glucosyl product phlorizin. We focused on aryl-C-glucosides and optimized the analogs, resulting in the discovery of canagliflozin, which is metabolically more stable than T-1095. Canagliflozin markedly induced UGE compared with that of T-1095 because of its excellent pharmacokinetic properties in vivo and its high potency for inhibiting SGLT2. Canagliflozin was selected as a clinical candidate for treating type 2 diabetes mellitus and was approved in the USA and EU in 2013 and in Japan in 2014. In this study, we describe the synthesis of new C-glucoside analogs using a palladium-catalyzed crosscoupling reaction of glucal boronate and its application as an SGLT2 inhibitor.

Original languageEnglish
Pages (from-to)877-884
Number of pages8
JournalYuki Gosei Kagaku Kyokaishi/Journal of Synthetic Organic Chemistry
Volume74
Issue number9
DOIs
Publication statusPublished - Jan 1 2016
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Organic Chemistry

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