Abstract
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.
MeSH terms
-
Animals
-
Benzhydryl Compounds / chemistry
-
Benzhydryl Compounds / pharmacokinetics
-
Benzhydryl Compounds / therapeutic use*
-
Diabetes Mellitus, Type 2 / drug therapy*
-
Glucosides / chemistry
-
Glucosides / pharmacokinetics
-
Glucosides / therapeutic use*
-
Humans
-
Macaca fascicularis
-
Magnetic Resonance Spectroscopy
-
Mice
-
Mice, Inbred ICR
-
Models, Molecular
-
Sodium-Glucose Transporter 2
-
Sodium-Glucose Transporter 2 Inhibitors*
-
Spectrometry, Mass, Electrospray Ionization
Substances
-
Benzhydryl Compounds
-
Glucosides
-
SLC5A2 protein, human
-
Sodium-Glucose Transporter 2
-
Sodium-Glucose Transporter 2 Inhibitors
-
6-((4-ethylphenyl)methyl)-3',4',5',6'-tetrahydro-6'-(hydroxymethyl)spiro(isobenzofuran-1(3H),2'-(2H)pyran)-3',4',5'-triol