C-Aryl 5a-carba-β-d-glucopyranosides as novel sodium glucose cotransporter 2 (SGLT2) inhibitors for the treatment of type 2 diabetes.
C-Aryl 5a-carba-β-d-glucopyranose derivatives were synthesized and evaluated for inhibition activity against hSGLT1 and hSGLT2. Modifications to the substituents on the two benzene rings resulted in enhanced hSGLT2 inhibition activity and extremely high hSGLT2 selectivity versus SGLT1. Using the created superimposed model, the reason for the high hSGLT2 selectivity was speculated to be that additional substituents occupied a new space, in a different way than known inhibitors. Among the tested compounds, the ethoxy compound 5h with high hSGLT2 selectivity exhibited more potent and longer hypoglycemic action in db/db mice than our O-carbasugar compound (1) and sergliflozin (2), which could be explained by its improved PK profiles relative to those of the two compounds. These results indicated that 5h might be a promising drug candidate for the treatment of type 2 diabetes.
Research Division, Fuji Gotemba Research Laboratory, Chugai Pharmaceutical Co. Ltd, 1-135 Komakado, Gotemba, Shizuoka 412-8513, Japan. ohtakeysh@chugai-pharm.co.jp
Yoshihito
Y
Ohtake
Tsutomu
T
Sato
Hiroharu
H
Matsuoka
Takamitsu
T
Kobayashi
Masahiro
M
Nishimoto
Naoki
N
Taka
Koji
K
Takano
Keisuke
K
Yamamoto
Masayuki
M
Ohmori
Takashi
T
Higuchi
Masatoshi
M
Murakata
Kazumi
K
Morikawa
Nobuo
N
Shimma
Masayuki
M
Suzuki
Hitoshi
H
Hagita
Kazuharu
K
Ozawa
Koji
K
Yamaguchi
Motohiro
M
Kato
Sachiya
S
Ikeda
D000284:Administration, Oral; D000818:Animals; D019540:Area Under Curve; D001786:Blood Glucose / Q000032:analysis; D003511:Cyclohexanols / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D005947:Glucose / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D007004:Hypoglycemic Agents / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D051379:Mice; D008820:Mice, Obese; D051297:Sodium-Glucose Transporter 2 / Q000378:metabolism; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D013329:Structure-Activity Relationship
C575514:4-(2-ethoxy-5-(4-ethylbenzyl)phenyl)-6-(hydroxymethyl)cyclohexane-1,2,3-triol; D001786:Blood Glucose; D003511:Cyclohexanols; D007004:Hypoglycemic Agents; D051297:Sodium-Glucose Transporter 2; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D005947:Glucose