RESUMO
A series of 2,5-diarylisothiazolones is reported that inhibit the IL-1 beta-induced breakdown of bovine nasal septum cartilage in an organ culture assay. The synthesis and preliminary SAR of these compounds are described. These compounds represent a novel, nonpeptide lead series approach to the mediation of the chronic cartilage breakdown associated with arthritic disease. These compounds are relatively resistant to reductive metabolism by liver microsomal preparations and appear to inhibit cartilage breakdown by interfering with the proteolytic activation of matrix metalloproteinases.
Assuntos
Cartilagem/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Interleucina-1/metabolismo , Tiazóis/farmacologia , Animais , Cartilagem/metabolismo , Bovinos , Hidrólise , Interleucina-1/antagonistas & inibidores , Espectroscopia de Ressonância Magnética , Técnicas de Cultura de Órgãos , Osteoartrite/metabolismo , Osteoartrite/prevenção & controle , Espectrofotometria Infravermelho , Relação Estrutura-Atividade , Tiazóis/químicaRESUMO
A series of 2-(arylmethyl)pyridoisothiazolones is reported that inhibit the IL-1 beta induced breakdown of bovine nasal septum cartilage in an organ culture assay. The synthesis and preliminary SAR of these compounds are described. These compounds represent a novel, non-peptide lead series approach to the mediation of the chronic cartilage breakdown associated with arthritic disease. These compounds are relatively resistant to reductive metabolism by liver microsomal preparations and appear to inhibit cartilage breakdown by interfering with the proteolytic activation of matrix metalloproteinases.
Assuntos
Cartilagem/metabolismo , Piridinas/farmacologia , Tiazóis/farmacologia , Animais , Bovinos , Indometacina/farmacologia , Interleucina-1/antagonistas & inibidores , Interleucina-1/metabolismo , Metaloproteinase 3 da Matriz , Metaloendopeptidases/antagonistas & inibidores , Metaloendopeptidases/metabolismo , Microssomos/metabolismo , Naproxeno/farmacologia , Septo Nasal , Técnicas de Cultura de Órgãos , Oxirredução/efeitos dos fármacos , Proteoglicanas/metabolismo , Pirazóis/farmacologia , Piridinas/síntese química , Piridinas/química , Relação Estrutura-Atividade , Tiazóis/síntese química , Tiazóis/químicaRESUMO
The synthesis, biological evaluation, and structure-activity relationships of a series of N-phenyl heteroaryl-fused isothiazolones are described. These isothiazolones have been shown to exhibit potent, dose-dependent inhibition of IL-1 beta-induced breakdown of proteoglycan in a cartilage organ culture assay. This effect is likely due to inhibition of MMP activation and a consequent reduction in MMP activity following IL-1 beta stimulation. Thus these compounds potentially represent simple, non-peptidic disease-modifying agents for the treatment of arthritic diseases. To examine the effects of structure on in vitro activity, three general features of the molecules were varied, substituents on the pendant N-phenyl group, the position of ring fusion to the isothiazolone, and substituents on the fused ring peri to the isothiazolone sulfur.
Assuntos
Cartilagem/efeitos dos fármacos , Cartilagem/metabolismo , Tiazóis/síntese química , Tiazóis/farmacologia , Animais , Bovinos , Relação Dose-Resposta a Droga , Humanos , Interleucina-1/antagonistas & inibidores , Interleucina-1/toxicidade , Isomerismo , Masculino , Metaloendopeptidases/farmacologia , Modelos Biológicos , Proteoglicanas/metabolismo , Piridinas/síntese química , Piridinas/farmacologia , Pirimidinas/síntese química , Pirimidinas/farmacologia , Ratos , Relação Estrutura-AtividadeRESUMO
The purpose of this study was to investigate the effects of cyclosporine A (CSA) and methotrexate (MTX) as potential immunomodulators in a nonestablished adjuvant arthritis (AA) model. Non-injected hind paw volumes were reduced when AA rats were treated for 18 days with CSA (100% at 10 mg/kg) or MTX (100% at 0.1 mg/kg). Body weights of drug treated AA rats were increased above untreated AA rats and were similar to non-arthritic controls. AA rats show elevated T helper (W3/25+)/T suppressor (OX 8+) cell ratios (2.0 vs. 3.1, p less than 0.01). The immunomodulators tested all returned these elevated ratios to control non-arthritic levels. Similarly, these drugs returned the reduced mitogen responses and elevated blood granulocyte numbers toward normal non-arthritic control values.
