Design, synthesis, and structure–activity relationships of a series of 4-benzyl-5-isopropyl-1H-pyrazol-3-yl β-d-glycopyranosides substituted with novel hydrophilic groups as highly potent inhibitors of sodium glucose co-transporter 1 (SGLT1)

• Published in: Bioorganic & medicinal chemistry 2013-02, Vol.21 (3), p.748-765
• Main Authors: Fushimi, Nobuhiko, Teranishi, Hirotaka, Shimizu, Kazuo, Yonekubo, Shigeru, Ohno, Kohsuke, Miyagi, Takashi, Itoh, Fumiaki, Shibazaki, Toshihide, Tomae, Masaki, Ishikawa-Takemura, Yukiko, Nakabayashi, Takeshi, Kamada, Noboru, Yamauchi, Yuji, Kobayashi, Susumu, Isaji, Masayuki
• Format: Article
• Language: English
• Subjects: absorption; acarbose; alpha-glucosidase; animal models; Diabetes; digestive system; Dose-Response Relationship, Drug; Drug Design; glucose; Glycosides - chemical synthesis; Glycosides - chemistry; Glycosides - pharmacology; Humans; hydrophilicity; Hydrophobic and Hydrophilic Interactions; hyperglycemia; metabolites; Molecular Structure; permeability; pharmacokinetics; Postprandial hyperglycemia; SGLT1; SGLT1 inhibitor; sodium; Sodium-Glucose Transporter 1 - antagonists & inhibitors; Structure-Activity Relationship; structure-activity relationships
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2012.11.041

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 therapeutic options for postprandial hyperglycemia. Previously, we reported potent and selective SGLT1 inhibitors 1 and 2 showing efficacy in oral carbohydrate tolerance tests in diabetic rat models. In a pharmacokinetic (PK) study of 2, excessive systemic exposure to metabolites of 2 was observed, presumably due to the high permeability of its aglycone (2a). To further improve SGLT1 inhibitory activity and reduce aglycone permeability, a series of 4-benzyl-5-isopropyl-1H-pyrazol-3-yl β-d-glycopyranoside derivatives bearing novel hydrophilic substitution groups on the phenyl ring were synthesized and their inhibitory activity toward SGLTs was evaluated. Optimized compound 14c showed an improved profile satisfying both higher activity and lower permeability of its aglycone (22f) compared with initial leads 1 and 2. Moreover, the superior efficacy of 14c in various carbohydrate tolerance tests in diabetic rat models was confirmed compared with acarbose, an α-glucosidase inhibitor (α-GI) widely used in the clinic.