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

• Published in: Bioorganic & medicinal chemistry Vol. 20; no. 22; pp. 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: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 15.11.2012; Elsevier
• Subjects: absorption; Animals; Biochemistry & Molecular Biology; Biological and medical sciences; blood glucose; Blood Glucose - analysis; Chemistry; Chemistry, Medicinal; Chemistry, Organic; Crystallography, X-Ray; Diabetes; Diabetes Mellitus, Experimental - drug therapy; digestive system; glucose; Glucosides - chemical synthesis; Glucosides - chemistry; Glucosides - therapeutic use; Humans; hyperglycemia; Hyperglycemia - drug therapy; Hypoglycemic Agents - chemical synthesis; Hypoglycemic Agents - chemistry; Hypoglycemic Agents - therapeutic use; Life Sciences & Biomedicine; Medical sciences; Molecular Conformation; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Physical Sciences; Postprandial hyperglycemia; Rats; Science & Technology; SGLT1; SGLT1 inhibitor; sodium; Sodium-Glucose Transporter 1 - antagonists & inhibitors; Sodium-Glucose Transporter 1 - metabolism; Sodium-Glucose Transporter 2 - antagonists & inhibitors; Sodium-Glucose Transporter 2 - metabolism; Structure-Activity Relationship; structure-activity relationships; Postprandial hyperglycemia; Diabetes; SGLT1; SGLT1 inhibitor; DRUG; TOLERANCE; ACARBOSE; RISK; DISCOVERY; CARDIOVASCULAR-DISEASE; PHLORHIZIN; ABSORPTION; REABSORPTION; EXPRESSION; Endocrinopathy; Postprandial; Diabetes mellitus; Benzene derivatives; Selectivity; Biological activity; Hyperglycemia; Treatment; Structure activity relation; glucose transporter; Pyrazole derivatives; Glycoside; Inhibitor; SGLT1 Na
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2012.09.037

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).