Assuntos
Inibidores de Ciclo-Oxigenase/farmacologia , Isoenzimas/antagonistas & inibidores , Isoenzimas/farmacologia , Isoxazóis/farmacologia , Prostaglandina-Endoperóxido Sintases/farmacologia , Acilação , Animais , Ciclo-Oxigenase 2 , Inibidores de Ciclo-Oxigenase 2 , Inibidores de Ciclo-Oxigenase/administração & dosagem , Cães , Injeções , Isoxazóis/administração & dosagem , Macaca fascicularis , Masculino , RatosAssuntos
Anti-Inflamatórios não Esteroides/síntese química , Inibidores Enzimáticos/síntese química , Isoenzimas/farmacologia , Isoxazóis/síntese química , Prostaglandina-Endoperóxido Sintases/farmacologia , Sulfonamidas/síntese química , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Artrite Experimental/tratamento farmacológico , Ciclo-Oxigenase 2 , Edema/tratamento farmacológico , Inibidores Enzimáticos/farmacologia , Humanos , Isoenzimas/sangue , Isoxazóis/farmacologia , Proteínas de Membrana , Prostaglandina-Endoperóxido Sintases/sangue , Ratos , Proteínas Recombinantes/antagonistas & inibidores , Sulfonamidas/farmacologiaRESUMO
A series of methysulfonyl or sulfonamido substituted 4,5-diaryloxazole were prepared and evaluated for their ability to inhibit the inducible form of cyclooxygenase (COX-2) in vitro and in vivo. Several unique substitution patterns were identified that led to potent and selective inhibitors of COX-2. In general, 2-trifluoromethly-4,5-diaryloxazoles substituted with a methylsulfonyl or sulfonamido group were particularly potent inhibitors. One of the more potent compounds with a selectivity for COX-2 of about 800 fold was 4b (SC-299). SC-299, a highly fluorescent molecule, may be useful for spectroscopic studies on preferential inhibitor binding to COX-2.
Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Inibidores de Ciclo-Oxigenase/farmacologia , Isoenzimas/efeitos dos fármacos , Oxazóis/farmacologia , Prostaglandina-Endoperóxido Sintases/efeitos dos fármacos , Animais , Ciclo-Oxigenase 2 , Inibidores de Ciclo-Oxigenase 2 , Humanos , Proteínas de MembranaRESUMO
A series of novel sulfone substituted 4,5-diarylthiazoles have been synthesized and evaluated for their inhibition of the two isoforms of human cyclooxygenase (COX-1 and COX-2). This series displays exceptionally selective COX-2 inhibition.
Assuntos
Isoenzimas/efeitos dos fármacos , Prostaglandina-Endoperóxido Sintases/efeitos dos fármacos , Sulfonas/química , Tiazóis/síntese química , Animais , Ciclo-Oxigenase 2 , Concentração Inibidora 50 , RatosRESUMO
A series of sulfonamide-substituted 4,5-diarylthiazoles was prepared via three synthetic routes as selective COX-2 inhibitors. Recently in the synthesis of selective COX-2 inhibitors we have discovered that the sulfonamide moiety is a suitable replacement for the methylsulfonyl moiety yielding compounds with activity both in vitro and in vivo.
Assuntos
Isoenzimas/efeitos dos fármacos , Prostaglandina-Endoperóxido Sintases/efeitos dos fármacos , Sulfonamidas/química , Tiazóis/síntese química , Animais , Ciclo-Oxigenase 2 , Inibidores de Ciclo-Oxigenase 2 , Inibidores de Ciclo-Oxigenase/síntese química , Humanos , Proteínas de Membrana , Modelos Químicos , RatosRESUMO
A series of sulfonamide-containing 1,5-diarylpyrazole derivatives were prepared and evaluated for their ability to block cyclooxygenase-2 (COX-2) in vitro and in vivo. Extensive structure-activity relationship (SAR) work was carried out within this series, and a number of potent and selective inhibitors of COX-2 were identified. Since an early structural lead (1f, SC-236) exhibited an unacceptably long plasma half-life, a number of pyrazole analogs containing potential metabolic sites were evaluated further in vivo in an effort to identify compounds with acceptable pharmacokinetic profiles. This work led to the identification of 1i (4-[5-(4-methylphenyl)-3-(trifluoromethyl)- H-pyrazol-1-yl]benzenesulfonamide, SC-58635, celecoxib), which is currently in phase III clinical trials for the treatment of rheumatoid arthritis and osteoarthritis.