新規<i>C</i>-グルコシド合成法の開発とSGLT2阻害薬への応用—SGLT2阻害薬カナグリフロジンの創製—

DOI Web Site Web Site 参考文献29件
  • 坂槇 茂輝
    田辺三菱製薬株式会社創薬本部腎・内分泌科学創薬ユニット
  • 川西 英治
    田辺三菱製薬株式会社創薬本部フロンティア疾患領域創薬ユニット
  • 野村 純宏
    田辺三菱製薬株式会社創薬本部腎・内分泌科学創薬ユニット

書誌事項

タイトル別名
  • Exploration of Novel <i>C</i>-Glucoside Formation and Application for SGLT2 Inhibitors —Discovery of Canagliflozin as a SGLT2 Inhibitor—
  • 新規C-グルコシド合成法の開発とSGLT2阻害薬への応用 : SGLT2阻害薬カナグリフロジンの創製
  • シンキ C-グルコシド ゴウセイホウ ノ カイハツ ト SGLT2 ソガイヤク エ ノ オウヨウ : SGLT2 ソガイヤク カナグリフロジン ノ ソウセイ

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説明

<p>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 cross-coupling reaction of glucal boronate and its application as an SGLT2 inhibitor.</p>

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