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
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
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.
Assuntos
Metaloproteinase 1 da Matriz/metabolismo , Inibidores de Metaloproteinases de Matriz , Inibidores de Proteases/síntese química , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Humanos , Ácidos Hidroxâmicos/química , Metaloproteinase 13 da Matriz , Metaloproteinases da Matriz/metabolismo , Inibidores de Proteases/farmacologia , Piranos/química , Relação Estrutura-Atividade , Sulfonamidas/químicaRESUMO
A series of novel MMP-13 and TNF-alpha converting enzyme inhibitors based on piperazine 2-hydroxamic acid scaffolds are described. The TACE, MMP-1 and MMP-13 activity of these inhibitors as well as the effect of substitution of the piperazine nitrogen and the P-1' benzyloxy tailpiece is discussed. Moderate in vivo activity is observed with several members of this group.
Assuntos
Inibidores Enzimáticos/síntese química , Inibidores de Metaloproteinases de Matriz , Metaloendopeptidases/antagonistas & inibidores , Piperazinas/síntese química , Fator de Necrose Tumoral alfa/metabolismo , Proteínas ADAM , Proteína ADAM17 , Animais , Colagenases/metabolismo , Inibidores Enzimáticos/farmacologia , Metaloproteinase 13 da Matriz , Metaloendopeptidases/metabolismo , Piperazinas/farmacologia , RatosRESUMO
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
A series of novel, selective TNF-alpha converting enzyme inhibitors based on 4-hydroxy and 5-hydroxy pipecolate hydroxamic acid scaffolds is described. The potency and selectivity of TACE inhibition is dramatically influenced by the nature of the sulfonamide group which interacts with the S1' site of the enzyme. Substituted 4-benzyloxybenzenesulfonamides exhibit excellent TACE potency with >100x selectivity over inhibition of matrix metalloprotease-1 (MMP-1). Alkyl substituents on the ortho position of the benzyl ether moiety give the most potent inhibition of TNF-alpha release in LPS-treated human whole blood.
