Structure–activity relationship studies of 4-benzyl-1H-pyrazol-3-yl β-d-glucopyranoside derivatives as potent and selective sodium glucose co-transporter 1 (SGLT1) inhibitors with therapeutic activity on postprandial hyperglycemia |
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Authors: | Nobuhiko Fushimi Hideki Fujikura Hiroaki Shiohara Hirotaka Teranishi Kazuo Shimizu Shigeru Yonekubo Kohsuke Ohno Takashi Miyagi Fumiaki Itoh Toshihide Shibazaki Masaki Tomae Yukiko Ishikawa-Takemura Takeshi Nakabayashi Noboru Kamada Tomonaga Ozawa Susumu Kobayashi Masayuki Isaji |
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Institution: | 1. Central Research Laboratory, Kissei Pharmaceutical Company, 4365-1 Kashiwabara, Hotaka, Azumino, Nagano Prefecture 399-8304, Japan;2. Faculty of Pharmaceutical Sciences, Tokyo University of Science (RIKADAI), 2641 Yamazaki, Noda-shi, Chiba Prefecture 278-8510, Japan |
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Abstract: | Sodium glucose co-transporter 1 (SGLT1) plays a dominant role in the absorption of glucose in the gut and is considered a promising target in the development of treatments for postprandial hyperglycemia. A series of 4-benzyl-1H-pyrazol-3-yl β-d-glucopyranoside derivatives have been synthesized, and its inhibitory activity toward SGLTs has been evaluated. By altering the substitution groups at the 5-position of the pyrazole ring, and every position of the phenyl ring, we studied the structure–activity relationship (SAR) profiles and identified a series of potent and selective SGLT1 inhibitors. Representative derivatives showed a dose-dependent suppressing effect on the escalation of blood glucose levels in oral mixed carbohydrate tolerance tests (OCTT) in streptozotocin–nicotinamide-induced diabetic rats (NA-STZ rats). |
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