RESUMO
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 N-hydroxycarbamates containing a histaminergic H(1) receptor antagonist pharmacophore was synthesized. In vitro assays determined the compounds had both histaminergic binding and 5-lipoxygenase inhibiting activities comparable to the corresponding N-hydroxyurea analog. Animal models demonstrated antihistaminergic and the 5-lipopxygenase inhibitory activity, with the N-hydroxyurea analog having a better overall profile.
Assuntos
Ácidos Hidroxâmicos/síntese química , Inibidores de Lipoxigenase , Animais , Sangue , Cobaias , Antagonistas dos Receptores Histamínicos H1/síntese química , Antagonistas dos Receptores Histamínicos H1/química , Humanos , Ácidos Hidroxâmicos/farmacologia , Concentração Inibidora 50 , Leucotrieno B4/biossíntese , Ligação Proteica , 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.
