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J Med Chem ; 39(20): 3920-8, 1996 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-8831758

RESUMO

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.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/síntese química , Pirazóis/síntese química , Absorção , Animais , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/sangue , Teste de Tolerância a Glucose , Glicosúria , Hipoglicemiantes/uso terapêutico , Túbulos Renais/metabolismo , Glicoproteínas de Membrana/antagonistas & inibidores , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Estrutura Molecular , Proteínas de Transporte de Monossacarídeos/antagonistas & inibidores , Pirazóis/farmacologia , Pirazóis/uso terapêutico , Ratos , Ratos Sprague-Dawley , Transportador 1 de Glucose-Sódio , Relação Estrutura-Atividade
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