Bioorganic & Medicinal Chemistry 2012-11-15

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.

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

Index: Bioorg. Med. Chem. 20(22) , 6598-612, (2012)

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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).Copyright © 2012 Elsevier Ltd. All rights reserved.