Discovery of Tofogliflozin, a Novel C-Arylglucoside with an O-Spiroketal Ring System, as a Highly Selective Sodium Glucose Cotransporter 2 (SGLT2) Inhibitor for the Treatment of Type 2 D
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- 作者：Yoshihito Ohtake ; Tsutomu Sato ; Takamitsu Kobayashi ; Masahiro Nishimoto ; Naoki Taka ; Koji Takano ; Keisuke Yamamoto ; Masayuki Ohmori ; Marina Yamaguchi ; Kyoko Takami ; Sang-Yong Yeu ; Koo-Hyeon Ahn ; Hiroharu Matsuoka ; Kazumi Morikawa ; Masayuki Suzuki ; Hitoshi Hagita ; Kazuharu Ozawa ; Koji Yamaguchi ; Motohiro Kato ; Sachiya Ikeda
- 刊名：Journal of Medicinal Chemistry
- 出版年：2012
- 出版时间：September 13, 2012
- 年：2012
- 卷：55
- 期：17
- 页码：7828-7840
- 全文大小：452K
- 年卷期：v.55,no.17(September 13, 2012)
- ISSN：1520-4804
文摘
Inhibition of sodium glucose cotransporter 2 (SGLT2) has been proposed as a novel therapeutic approach to treat type 2 diabetes. In our efforts to discover novel inhibitors of SGLT2, we first generated a 3D pharmacophore model based on the superposition of known inhibitors. A search of the Cambridge Structural Database using a series of pharmacophore queries led to the discovery of an O-spiroketal C-arylglucoside scaffold. Subsequent chemical examination combined with computational modeling resulted in the identification of the clinical candidate 16d (CSG452, tofogliflozin), which is currently under phase III clinical trials.