Discovery of tofogliflozin, a novel C-arylglucoside with an O-spiroketal ring system, as a highly selective sodium glucose cotransporter 2 (SGLT2) inhibitor for the treatment of type 2 diabetes.
Inhibition of sodium glucose cotransporter 2 (SGLT2) has been proposed as a novel therapeutic approach to treat type 2 diabetes. In our efforts to discover novel inhibitors of SGLT2, we first generated a 3D pharmacophore model based on the superposition of known inhibitors. A search of the Cambridge Structural Database using a series of pharmacophore queries led to the discovery of an O-spiroketal C-arylglucoside scaffold. Subsequent chemical examination combined with computational modeling resulted in the identification of the clinical candidate 16d (CSG452, tofogliflozin), which is currently under phase III clinical trials.
Research Division, Chugai Pharmaceutical Co., Ltd., 1-135 Komakado, Gotemba, Shizuoka 412-8513, Japan. ohtakeysh@chugai-pharm.co.jp
Yoshihito
Y
Ohtake
Tsutomu
T
Sato
Takamitsu
T
Kobayashi
Masahiro
M
Nishimoto
Naoki
N
Taka
Koji
K
Takano
Keisuke
K
Yamamoto
Masayuki
M
Ohmori
Marina
M
Yamaguchi
Kyoko
K
Takami
Sang-Yong
SY
Yeu
Koo-Hyeon
KH
Ahn
Hiroharu
H
Matsuoka
Kazumi
K
Morikawa
Masayuki
M
Suzuki
Hitoshi
H
Hagita
Kazuharu
K
Ozawa
Koji
K
Yamaguchi
Motohiro
M
Kato
Sachiya
S
Ikeda
D000818:Animals; D001559:Benzhydryl Compounds / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D005960:Glucosides / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D006801:Humans; D008252:Macaca fascicularis; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008813:Mice, Inbred ICR; D008958:Models, Molecular; D051297:Sodium-Glucose Transporter 2; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D021241:Spectrometry, Mass, Electrospray Ionization
D001559:Benzhydryl Compounds; D005960:Glucosides; C089180:SLC5A2 protein, human; D051297:Sodium-Glucose Transporter 2; D000077203:Sodium-Glucose Transporter 2 Inhibitors; C575086:6-((4-ethylphenyl)methyl)-3',4',5',6'-tetrahydro-6'-(hydroxymethyl)spiro(isobenzofuran-1(3H),2'-(2H)pyran)-3',4',5'-triol