C-Glucosides with heteroaryl thiophene as novel sodium-dependent glucose cotransporter 2 inhibitors
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- 作者：Yuichi Koga ; Shigeki Sakamaki ; Mitsuya Hongu ; Eiji Kawanishi ; Toshiaki Sakamoto ; Yasuo Yamamoto ; Hirotaka Kimata ; Keiko Nakayama ; Chiaki Kuriyama ; Yasuaki Matsushita ; Kiichiro Ueta ; Minoru Tsuda-Tsukimoto ; Sumihiro Nomura
- 关键词：Type 2 diabetes ; SGLT2 inhibitor ; Thiophene ; Glucoside ; Canagliflozin
- 刊名：Bioorganic and Medicinal Chemistry
- 出版年：2013
- 出版时间：1 September, 2013
- 年：2013
- 卷：21
- 期：17
- 页码：5561-5572
- 全文大小：1523 K
文摘
Canagliflozin (1), a novel inhibitor for sodium-dependent glucose cotransporter 2 (SGLT2), has been developed for the treatment of type 2 diabetes. To investigate the effect of replacement of the phenyl ring in 1 with heteroaromatics, C-glucosides 2 were designed, synthesized, and evaluated for their inhibitory activities against SGLT2. Of these, 3-pyridyl, 2-pyrimidyl or 5-membered heteroaryl substituted derivatives showed highly potent inhibitory activity against SGLT2, while 5-pyrimidyl substitution was associated with slightly reduced activity. In particular, 2g (TA-3404) had remarkable anti-hyperglycemic effects in high-fat diet fed KK (HF-KK) mice.