New potent antihyperglycemic agents in db/db mice: synthesis and structure-activity relationship studies of (4-substituted benzyl) (trifluoromethyl)pyrazoles and -pyrazolones

J Med Chem. 1996 Sep 27;39(20):3920-8. doi: 10.1021/jm960444z.


The synthesis, structure-activity relationship (SAR) studies, and antidiabetic characterization of 1,2-dihydro-4-[[4-(methylthio)phenyl]methyl]-5-(trifluoromethyl)-3H- pyrazol-3-one (as the hydroxy tautomer; WAY-123783, 4) are described. Substitution of 4-methylthio, methylsulfinyl, or ethyl to a benzyl group at C4, in combination with trifluoromethyl at C5 of pyrazol-3-one, generated potent antihyperglycemic agents in obese, diabetic db/db mice (16-30% reduction in plasma glucose at 2 mg/kg). The antihyperglycemic effect was associated with a robust glucosuria (> 8 g/dL) observed in nondiabetic mice. Chemical trapping of four of the seven possible tautomeric forms of the heterocycle by mono- and dialkylation at the acidic hydrogens provided several additional potent analogs (39-43% reduction at 5 mg/kg) of the lead 4 as well as a dialkylated pair of regioisomers that showed separation of the associated glucosuric effect produced by all of the active analogs in normal mice. Further pharmacological characterization of the lead WAY-123783 (ED50 = 9.85 mg/kg, po in db/db mice), in oral and subcutaneous glucose tolerance tests, indicated that unlike the renal and intestinal glucose absorption inhibitor phlorizin, pyrazolone 4 does not effectively block intestinal glucose absorption. SAR and additional pharmacological data reported herein suggest that WAY-123783 represents a new class of potent antihyperglycemic agents which correct hyperglycemia by selective inhibition of renal tubular glucose reabsorption.

MeSH terms

  • Absorption
  • Animals
  • Blood Glucose / metabolism
  • Diabetes Mellitus, Type 2 / blood
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Glucose Tolerance Test
  • Glycosuria
  • Hypoglycemic Agents / chemical synthesis*
  • Hypoglycemic Agents / therapeutic use
  • Kidney Tubules / metabolism
  • Membrane Glycoproteins / antagonists & inhibitors
  • Mice
  • Mice, Inbred C57BL
  • Mice, Obese
  • Molecular Structure
  • Monosaccharide Transport Proteins / antagonists & inhibitors
  • Pyrazoles / chemical synthesis*
  • Pyrazoles / pharmacology
  • Pyrazoles / therapeutic use
  • Rats
  • Rats, Sprague-Dawley
  • Sodium-Glucose Transporter 1
  • Structure-Activity Relationship


  • Blood Glucose
  • Hypoglycemic Agents
  • Membrane Glycoproteins
  • Monosaccharide Transport Proteins
  • Pyrazoles
  • Slc5a1 protein, mouse
  • Sodium-Glucose Transporter 1
  • WAY 123783