C-Glucosides with heteroaryl thiophene as novel sodium-dependent glucose cotransporter 2 inhibitors |
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| Authors: | 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 |
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| Institution: | 1. Medicinal Chemistry Research Laboratories, Mitsubishi Tanabe Pharma Corporation, 2-2-50 Kawagishi, Toda, Saitama 335-8505, Japan;2. Pharmacology Research Laboratories, Mitsubishi Tanabe Pharma Corporation, 2-2-50 Kawagishi, Toda, Saitama 335-8505, Japan;3. DMPK Research Laboratories, Mitsubishi Tanabe Pharma Corporation, 2-2-50 Kawagishi, Toda, Saitama 335-8505, Japan |
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| Abstract: | 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. |
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| Keywords: | Type 2 diabetes SGLT2 inhibitor Thiophene Glucoside Canagliflozin |
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