RESUMO
2,2-dimethyl-4-phenyl-5-[4-(methylsulfinyl)phenyl]-3(2H)furanone derivatives, 3 and 6, were shown to be effectively transformed in vivo into the corresponding methylsulfone derivatives 1 and 4, when orally administered to rats. Pharmacological implications for use of sulfoxide analogues 3 and 6 are discussed as prodrugs to potent selective COX-2 inhibitors 1 and 4.
Assuntos
Inibidores de Ciclo-Oxigenase/administração & dosagem , Pró-Fármacos/administração & dosagem , Sulfonas/administração & dosagem , Animais , Inibidores de Ciclo-Oxigenase/química , Dimetil Sulfóxido , Relação Dose-Resposta a Droga , Masculino , Pró-Fármacos/química , Ratos , Ratos Endogâmicos Lew , Ratos Sprague-Dawley , Sulfonas/químicaRESUMO
5-Aryl-2,2-dialkyl-4-phenyl-3(2H)furanone derivatives were studied as a novel class of selective cyclooxygenase-2 inhibitors with regard to synthesis, in vitro SAR, antiinflammatory activities, pharmacokinetic considerations, and gastric safety. 1f, a representative compound for methyl sulfone derivatives, showed a COX-2 IC(50) comparable to that of rofecoxib. In case of 20b, a representative compound for sulfonamide derivatives, a potent antiinflammatory ED(50) of 0.1 mg kg(-1) day(-1) was observed against adjuvant-induced arthritis by a preventive model, positioning 20b as one of the most potent COX-2 inhibitors ever reported. Furthermore, 20b showed strong analgesic activity as indicated by its ED(50) of 0.25 mg/kg against carrageenan-induced thermal hyperalgesia in the Sprague-Dawley rat. 3(2H)Furanone derivatives showed due gastric safety profiles as selective COX-2 inhibitors upon 7-day repeat dosing. A highly potent COX-2 inhibitor of the 3(2H)furanone scaffold could be considered suitable for a future generation COX-2 selective arthritis medication with improved safety profiles.
Assuntos
Inibidores de Ciclo-Oxigenase/síntese química , Furanos/síntese química , Isoenzimas/antagonistas & inibidores , Adulto , Animais , Artrite Experimental/tratamento farmacológico , Carragenina , Ciclo-Oxigenase 1 , Ciclo-Oxigenase 2 , Inibidores de Ciclo-Oxigenase 2 , Inibidores de Ciclo-Oxigenase/farmacologia , Inibidores de Ciclo-Oxigenase/toxicidade , Edema/induzido quimicamente , Edema/tratamento farmacológico , Furanos/farmacologia , Furanos/toxicidade , Humanos , Técnicas In Vitro , Isoenzimas/sangue , Isoenzimas/metabolismo , Macrófagos Peritoneais/efeitos dos fármacos , Macrófagos Peritoneais/enzimologia , Masculino , Proteínas de Membrana , Camundongos , Modelos Moleculares , Prostaglandina-Endoperóxido Sintases/sangue , Prostaglandina-Endoperóxido Sintases/metabolismo , Ratos , Ratos Sprague-Dawley , Úlcera Gástrica/induzido quimicamente , Relação Estrutura-AtividadeRESUMO
Twenty-seven N,N',N"-trisubstituted thiourea derivatives were prepared. Among them, 1-[3-(4'-hydroxy-3'-methoxy-phenyl)-propyl]-1,3-diphenethyl-thiourea (8l, IC(50)=0.32 microM), showed 2-fold higher antagonistic activity than that of capsazepine (3, IC(50)=0.65 microM) against the vanilloid receptor in a (45)Ca(2+)-influx assay.
