RESUMO
The synthesis, structure-activity relationship, in vivo activity, and metabolic profile for a series of triazolopyridine-oxazole based p38 inhibitors are described. The deficiencies of the lead structure in the series, CP-808844, were overcome by changes to the C4 aryl group and the triazole side-chain culminating in the identification of several potential clinical candidates.
Assuntos
Inibidores Enzimáticos/farmacologia , Oxazóis/química , Piridinas/química , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Proteínas Quinases p38 Ativadas por Mitógeno/química , Química Farmacêutica , Desenho de Fármacos , Inibidores Enzimáticos/química , Humanos , Concentração Inibidora 50 , Cinética , Modelos Químicos , Solubilidade , Relação Estrutura-Atividade , Triazóis/químicaRESUMO
Mimics of the benzimidazolone nucleus found in inhibitors of p38 kinase are proposed, and their theoretical potential as bioisosteres is described. A set of calculated descriptors relevant to the anticipated binding interaction for the fragments 1-methyl-1H-benzotriazole 5, 3-methyl-benzo[d]isoxazole 3, and 3-methyl-[1,2,4]triazolo[4,3-a]pyridine 4, pyridine 1, and 1,3-dimethyl-1,3-dihydro-benzoimidazol-2-one 2 are reported. The design considerations and synthesis of p38 inhibitors based on these H-bond acceptor fragments is detailed. Comparative evaluation of the pyridine-, benzimidazolone-, benzotriazole-, and triazolopyridine-based inhibitors shows the triazoles 20 and 25 to be significantly more potent experimentally than the benzimidazolone after which they were modeled. An X-ray crystal structure of 25 bound to the active site shows that the triazole group serves as the H-bond acceptor but unexpectedly as a dual acceptor, inducing movement of the crossover connection of p38alpha. The computed descriptors for the hydrophobic and pi-pi interaction capacities were the most useful in ranking potency.
Assuntos
Benzimidazóis/química , Piridinas/química , Triazóis/química , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Proteínas Quinases p38 Ativadas por Mitógeno/química , Benzimidazóis/síntese química , Sítios de Ligação , Cristalografia por Raios X , Ligação de Hidrogênio , Interações Hidrofóbicas e Hidrofílicas , Modelos Moleculares , Mimetismo Molecular , Estrutura Molecular , Ligação Proteica , Piridinas/síntese química , Relação Quantitativa Estrutura-Atividade , Eletricidade Estática , Triazóis/síntese químicaRESUMO
A series of 3-hydroxy-3-methylpipecolic hydroxamate inhibitors of MMP-13 and aggrecanase was designed based on the observation of increased aggrecanase activity with substitution at the 3-position of the piperidine ring. Potency versus aggrecanase was optimized by modification of the benzyloxyarylsulfonamide group that binds in the S1' pocket. These compounds also possess markedly improved bioavailability and lower metabolic clearance compared to analogous 3,3-dimethyl-5-hydroxypipecolic hydroxamates. These improvements are attributed to lowered lipophilicity proximal to the metabolically labile hydroxamic acid. Synthesis, structure activity relationships, and in vivo efficacy data are described.
Assuntos
Endopeptidases/efeitos dos fármacos , Ácidos Hidroxâmicos/síntese química , Ácidos Hidroxâmicos/farmacocinética , Inibidores de Metaloproteinases de Matriz , Ácidos Pipecólicos/síntese química , Ácidos Pipecólicos/farmacocinética , Administração Oral , Animais , Colagenases/metabolismo , Desenho de Fármacos , Endopeptidases/metabolismo , Humanos , Ácidos Hidroxâmicos/química , Metaloproteinase 13 da Matriz , Estrutura Molecular , Ácidos Pipecólicos/química , Inibidores de Proteases/síntese química , Inibidores de Proteases/química , Inibidores de Proteases/farmacocinética , Relação Estrutura-AtividadeRESUMO
The synthesis and in vitro p38 alpha activity of a novel series of benzimidazolone inhibitors is described. The p38 alpha SAR is consistent with a mode of binding wherein the benzimidazolone carbonyl serves as the H-bond acceptor to Met109 of p38 alpha in a manner analogous to the pyridine nitrogen of prototypical pyridylimidazole p38 inhibitors. Potent p38 alpha activity comparable to that of several previously reported p38 inhibitors is observed for this novel chemotype.
Assuntos
Benzimidazóis/farmacologia , Inibidores Enzimáticos/farmacologia , Proteínas Quinases Ativadas por Mitógeno/antagonistas & inibidores , Benzimidazóis/síntese química , Inibidores Enzimáticos/síntese química , Imidazóis/farmacologia , Proteína Quinase 14 Ativada por Mitógeno , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Estrutura Molecular , Piridinas/farmacologia , Relação Estrutura-AtividadeRESUMO
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
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.
