181795-82-4Relevant academic research and scientific papers
New potent antihyperglycemic agents in db/db mice: Synthesis and structure-activity relationship studies of (4-substituted benzyl)(trifluoromethyl)pyrazoles and -pyrazolones
Kees, Kenneth L.,Fitzgerald Jr., John J.,Steiner, Kurt E.,Mattes, James F.,Mihan, Brenda,Tosi, Theresa,Mondoro, Diane,McCaleb, Michael L.
, p. 3920 - 3928 (2007/10/03)
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.
