title: 5a-Carba-β-D-glucopyranose derivatives as novel sodium-dependent glucose cotransporter 2 (SGLT2) inhibitors for the treatment of type 2 diabetes.
abstract: 5a-Carba-β-D-glucopyranose derivatives were synthesized and identified as novel SGLT2-selective inhibitors. These inhibitors exhibited potent SGLT2 inhibition with high selectivity over SGLT1. Among the tested compounds, 6f indicated the most potent hSGLT2 inhibition and the highest selectivity over hSGLT1. Moreover, the pharmacokinetics data also showed that 6h, which had the same aglycon structure as sergliflozin-active (3-active), had a threefold longer half-life time (T(1/2)) than sergliflozin (3) with a high distribution volume in db/db mice. Subsequently, 6h lowered blood glucose levels as much as 3 and showed longer hypoglycemic action than 3 in db/db mice.
authors.affiliation: Research Division, Fuji Gotemba Research Laboratory, Chugai Pharmaceutical Co., Ltd, 1-135, Komakado, Gotemba, Shizuoka 412-8513, Japan. ohtakeysh@chugai-pharm.co.jp
authors.forename: Yoshihito
authors.initials: Y
authors.lastname: Ohtake
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Sato
authors.forename: Hiroharu
authors.initials: H
authors.lastname: Matsuoka
authors.forename: Masahiro
authors.initials: M
authors.lastname: Nishimoto
authors.forename: Naoki
authors.initials: N
authors.lastname: Taka
authors.forename: Koji
authors.initials: K
authors.lastname: Takano
authors.forename: Keisuke
authors.initials: K
authors.lastname: Yamamoto
authors.forename: Masayuki
authors.initials: M
authors.lastname: Ohmori
authors.forename: Takashi
authors.initials: T
authors.lastname: Higuchi
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Murakata
authors.forename: Takamitsu
authors.initials: T
authors.lastname: Kobayashi
authors.forename: Kazumi
authors.initials: K
authors.lastname: Morikawa
authors.forename: Nobuo
authors.initials: N
authors.lastname: Shimma
authors.forename: Masayuki
authors.initials: M
authors.lastname: Suzuki
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Hagita
authors.forename: Kazuharu
authors.initials: K
authors.lastname: Ozawa
authors.forename: Koji
authors.initials: K
authors.lastname: Yamaguchi
authors.forename: Motohiro
authors.initials: M
authors.lastname: Kato
authors.forename: Sachiya
authors.initials: S
authors.lastname: Ikeda
mesh_terms: D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy*; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D005947:Glucose / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D008297:Male; D051379:Mice; D008820:Mice, Obese; D008968:Molecular Conformation; D008969:Molecular Sequence Data; D051297:Sodium-Glucose Transporter 2 / Q000378:metabolism; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014018:Tissue Distribution
chemical_list: C089180:SLC5A2 protein, human; D051297:Sodium-Glucose Transporter 2; D000077203:Sodium-Glucose Transporter 2 Inhibitors; C048030:5-hydroxymethyl-1,2,3,4-cyclohexanetetrol; D005947:Glucose