NEW POTENT ANTIHYPERGLYCEMIC AGENTS IN DB DB MICE - SYNTHESIS AND STRUCTURE-ACTIVITY RELATIONSHIP STUDIES OF (4-SUBSTITUTED BENZYL)(TRIFLUOROMETHYL)PYRAZOLES AND (4-SUBSTITUTED BENZYL)(TRIFLUOROMETHYL)PYRAZOLONES/

The synthesis, structure-activity relationship (SAR) studies, and anti diabetic characterization of henyl]methyl]-5-(trifluoromethyl)-3H-pyra zol-3-one (as the hydroxy tautomer; WAY-123783, 4) are described. Subs titution of 4-methylthio, methylsulfinyl, or ethyl to a benzyl group a t C-4, in combination with trifluoromethyl at C-5 Of pyrazol-3-one, ge nerated 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 taut omeric forms of the heterocycle by mono- and dialkylation at the acidi c hydrogens provided several additional potent analogs (39-43% reducti on at 5 mg/kg) of the lead 4 as well as a dialkylated pair of regioiso mers that showed separation of the associated glucosuric effect produc ed by all of the active analogs in normal mice. Further pharmacologica l characterization of the lead WAY-123783 (ED(50) = 9.85 mg/kg, po in db/db mice), in oral and subcutaneous glucose tolerance tests, indicat ed that unlike the renal and intestinal glucose absorption inhibitor p hlorizin, pyrazolone 4 does not effectively block intestinal glucose a bsorption. SAR and additional pharmacological data reported herein sug gest that WAY-123783 represents a new class of potent antihyperglycemi c agents which correct hyperglycemia by selective inhibition of renal tubular glucose reabsorption.