RESUMO
Inhibitors of matrix metalloprotease (MMP)-13 and tumor necrosis factor-alpha converting enzyme (TACE) have been highly sought as potential therapeutic agents for the treatment of osteoarthritis and rheumatoid arthritis, respectively. This review focuses on the published literature on these inhibitors from 2001 to mid-2003. Significant advances have been reported in the design and synthesis of potent and selective inhibitors of MMP-13 using hydroxamic acid and non-hydroxamate zinc chelators on a variety of scaffolds. TACE inhibitors based on variations of known MMP inhibitors scaffolds and novel designs have been reported. Selectivity profiles for these inhibitors range from broad-spectrum to TACE-specific. Future clinical studies on these and other inhibitors will determine which MMP, or set of MMPs, must be inhibited for efficacy and long-term safety.
Assuntos
Inibidores de Metaloproteinases de Matriz , Metaloendopeptidases/antagonistas & inibidores , Inibidores de Proteases/química , Inibidores de Proteases/síntese química , Proteínas ADAM , Proteína ADAM17 , Animais , Artrite Reumatoide/tratamento farmacológico , Quelantes , Desenho de Fármacos , Humanos , Ácidos Hidroxâmicos/síntese química , Metaloproteinase 13 da Matriz , Osteoartrite/tratamento farmacológico , Inibidores de Proteases/uso terapêutico , Relação Estrutura-Atividade , ZincoRESUMO
Modification of alpha-biphenylsulfonamidocarboxylic acids led to potent and selective MMP-13 inhibitors. Compound 16 showed 100% oral bioavailability in rats and demonstrated >50% inhibition of bovine cartilage degradation at 10 ng/mL.
Assuntos
Colagenases/metabolismo , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/farmacocinética , Inibidores de Metaloproteinases de Matriz , Osteoartrite/tratamento farmacológico , Administração Oral , Animais , Benzofuranos/síntese química , Benzofuranos/química , Colagenases/química , Avaliação Pré-Clínica de Medicamentos , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/química , Concentração Inibidora 50 , Metaloproteinase 13 da Matriz , Modelos Moleculares , Estrutura Molecular , Ratos , Especificidade por SubstratoRESUMO
A series of highly potent thiourea inhibitors of cytomegalovirus (CMV) with improved stability properties was prepared and evaluated. Compound 29 inhibited the virus in cultured HFF cells with IC50 of 0.2 nM.
Assuntos
Antivirais/síntese química , Citomegalovirus/efeitos dos fármacos , Herpesviridae/efeitos dos fármacos , Tioureia/análogos & derivados , Antivirais/farmacologia , Células Cultivadas , Resistência Microbiana a Medicamentos , Humanos , Concentração Inibidora 50 , Relação Estrutura-Atividade , Tioureia/farmacologiaRESUMO
Bis-(aryl)thioureas were found to be potent and selective inhibitors of cytomegalovirus (CMV) in cultured HFF cells. Of these, the thiazole analogue 38 was investigated as a potential development candidate.