RESUMO
Explorations in the pyrimidinetrione series of MMP-13 inhibitors led to the discovery of a series of spiro-fused compounds that are potent and selective inhibitors of MMP-13. While other spiro-fused motifs are hydrolytically unstable, presumably due to electronic destabilization of the pyrimidinetrione ring, the spiropyrrolidine series does not share this liability. Greater than 100-fold selectivity versus other MMP family members was achieved by incorporation of an extended aryl-heteroaryl P1'group. When dosed as the sodium salt, these compounds displayed excellent oral absorption and pharmacokinetic properties. Despite the selectivity, a representative of this series produced fibroplasia in a 14 day rat study.
Assuntos
Inibidores de Metaloproteinases de Matriz , Inibidores de Proteases/química , Pirimidinas/química , Pirrolidinas/química , Compostos de Espiro/química , Animais , Estabilidade Enzimática/efeitos dos fármacos , Metaloproteinase 13 da Matriz/metabolismo , Inibidores de Proteases/farmacologia , Pirimidinas/farmacologia , Pirrolidinas/farmacologia , Ratos , Compostos de Espiro/farmacologia , Relação Estrutura-AtividadeRESUMO
Through the use of computational modeling, a series of pyrimidinetrione-based inhibitors of MMP-13 was designed based on a lead inhibitor identified through file screening. Incorporation of a biaryl ether moiety at the C-5 position of the pyrimidinetrione ring resulted in a dramatic enhancement of MMP-13 potency. Protein crystallography revealed that this moiety binds in the S(1)(') pocket of the enzyme. Optimization of the C-4 substituent of the terminal aromatic ring led to incorporation of selectivity versus MMP-14 (MT-1 MMP). Structure activity relationships of the biaryl ether substituent are presented as is pharmacokinetic data for a compound that meets our in vitro potency and selectivity goals.
Assuntos
Inibidores Enzimáticos/síntese química , Inibidores de Metaloproteinases de Matriz , Pirimidinas/química , Sítios de Ligação , Colagenases/química , Cristalografia por Raios X , Inibidores Enzimáticos/farmacologia , Metaloproteinase 13 da Matriz , Relação Estrutura-AtividadeRESUMO
The SAR of a series of sterically hindered sulfonamide hydroxamic acids with relatively large P1' groups is described. The compounds typically spare MMP-1 while being potent inhibitors of MMP-13. The metabolically more stable compounds in the series contain either a monocyclic or bicyclic pyran ring adjacent to the hydroxamate group. Despite the sparing of MMP-1, pre-clinical and clinical studies revealed that fibrosis in rats and MSS in humans is still produced.
