RESUMO
Novel hygromycin A derivatives bearing a variety of functionalized aminocyclitol moieties have been synthesized in an effort to increase the antibacterial activity and drug-like properties of this class of agents. A systematic study of the effect of alkylation and removal of the hydroxyls of the aminocyclitol directed us to a series of alkylated aminocyclitol derivatives with improved gram-positive activity.
Assuntos
Antibacterianos/síntese química , Antibacterianos/farmacologia , Cinamatos/síntese química , Cinamatos/farmacologia , Higromicina B/análogos & derivados , Higromicina B/síntese química , Higromicina B/farmacologia , Testes de Sensibilidade MicrobianaRESUMO
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
Using SAR from two related series of pyrimidinetrione-based inhibitors, compounds with potent MMP-13 inhibition and >100-fold selectivity against other MMPs have been identified. Despite high molecular weights, clogPs, and polar surface areas, the compounds are generally well absorbed and have excellent pharmacokinetic (PK) properties when dosed as sodium salts. In a rat fibrosis model, a compound from the series displayed no fibrosis at exposures many fold greater than its MMP-13 IC50.
Assuntos
Inibidores de Metaloproteinases de Matriz , Inibidores de Proteases/síntese química , Inibidores de Proteases/farmacologia , Pirimidinonas/química , Animais , Fibrose/tratamento farmacológico , Fibrose/patologia , Ácidos Hidroxâmicos/química , Concentração Inibidora 50 , Peso Molecular , Ratos , Sais/química , Sódio/química , Relação Estrutura-AtividadeRESUMO
Phosphinic acid-based inhibitors of MMP-13 have been investigated with the aim of identifying potent inhibitors with high selectivity versus MMP-1. Independent variation of the substituents on a P(1)' phenethyl group and a P(2) benzyl group improved potencies in both cases around 3-fold over the unsubstituted parent. Combining improved P(1)' and P(2) groups into a single molecule gave an inhibitor with a 4.5 nM IC(50) against MMP-13 and which is 270-fold selective over MMP-1.
Assuntos
Metaloproteinase 1 da Matriz/efeitos dos fármacos , Metaloproteinase 3 da Matriz/efeitos dos fármacos , Inibidores de Metaloproteinases de Matriz , Ácidos Fosfínicos/química , Ácidos Fosfínicos/farmacologia , Inibidores de Proteases/síntese química , Inibidores de Proteases/farmacologia , Colagenases/química , Indicadores e Reagentes , Isomerismo , Metaloproteinase 1 da Matriz/química , Metaloproteinase 13 da Matriz , Metaloproteinase 3 da Matriz/química , Relação Estrutura-Atividade , Especificidade por SubstratoRESUMO
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.