title: 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).
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 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.
authors.affiliation: Central Research Laboratory, Kissei Pharmaceutical Company, 4365-1 Kashiwabara, Hotaka, Azumino, Nagano Prefecture 399-8304, Japan. nobuhiko_fushimi@pharm.kissei.co.jp
authors.forename: Nobuhiko
authors.initials: N
authors.lastname: Fushimi
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Teranishi
authors.forename: Kazuo
authors.initials: K
authors.lastname: Shimizu
authors.forename: Shigeru
authors.initials: S
authors.lastname: Yonekubo
authors.forename: Kohsuke
authors.initials: K
authors.lastname: Ohno
authors.forename: Takashi
authors.initials: T
authors.lastname: Miyagi
authors.forename: Fumiaki
authors.initials: F
authors.lastname: Itoh
authors.forename: Toshihide
authors.initials: T
authors.lastname: Shibazaki
authors.forename: Masaki
authors.initials: M
authors.lastname: Tomae
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Ishikawa-Takemura
authors.forename: Takeshi
authors.initials: T
authors.lastname: Nakabayashi
authors.forename: Noboru
authors.initials: N
authors.lastname: Kamada
authors.forename: Yuji
authors.initials: Y
authors.lastname: Yamauchi
authors.forename: Susumu
authors.initials: S
authors.lastname: Kobayashi
authors.forename: Masayuki
authors.initials: M
authors.lastname: Isaji
mesh_terms: D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006027:Glycosides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D015394:Molecular Structure; D051269:Sodium-Glucose Transporter 1 / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
chemical_list: D006027:Glycosides; C495674:SLC5A1 protein, human; D051269:Sodium-Glucose Transporter 1