Structure-activity relationship studies of 4-benzyl-1H-pyrazol-3-yl I2-d-glucopyranoside derivatives as potent and selective sodium glucose co-transporter 1 (SGLT1) inhibitors with therapeutic activity on postprandial hyperglycemia

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 I2-d-glucopyranoside derivatives have been synthesized, and...

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Published in:Bioorganic & medicinal chemistry 2012-11, Vol.20 (22), p.6598-6612
Main Authors: Fushimi, Nobuhiko, Fujikura, Hideki, Shiohara, Hiroaki, Teranishi, Hirotaka, Shimizu, Kazuo, Yonekubo, Shigeru, Ohno, Kohsuke, Miyagi, Takashi, Itoh, Fumiaki, Shibazaki, Toshihide, Tomae, Masaki, Ishikawa-Takemura, Yukiko, Nakabayashi, Takeshi, Kamada, Noboru, Ozawa, Tomonaga, Kobayashi, Susumu, Isaji, Masayuki
Format: Article
Language:English
Subjects:
Blood
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Summary: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 I2-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 streptozotocinanicotinamide-induced diabetic rats (NA-STZ rats).
ISSN:0968-0896
DOI:10.1016/j.bmc.2012.09.037