RESUMO
A new class of chymase inhibitor featuring a benzimidazolone core with an acid side chain and a P(1) hydrophobic moiety is described. Incubation of the lead compound with GSH resulted in the formation of a GSH conjugate on the benzothiophene P(1) moiety. Replacement of the benzothiophene with different heterocyclic systems such as indoles and benzoisothiazole is feasible. Among the P(1) replacements, benzoisothiazole prevents the formation of GSH conjugate and an in silico analysis of oxidative potentials agreed with the experimental outcome.
Assuntos
Benzimidazóis/química , Quimases/antagonistas & inibidores , Inibidores de Proteases/química , Benzimidazóis/metabolismo , Benzimidazóis/farmacologia , Sítios de Ligação , Quimases/metabolismo , Cristalografia por Raios X , Humanos , Interações Hidrofóbicas e Hidrofílicas , Oxirredução , Inibidores de Proteases/síntese química , Inibidores de Proteases/farmacologia , Estrutura Terciária de Proteína , Relação Estrutura-AtividadeRESUMO
Interleukin-2 inducible T-cell kinase (ITK) is a member of the Tec kinase family and is involved with T-cell activation and proliferation. Due to its critical role in acting as a modulator of T-cells, ITK inhibitors could provide a novel route to anti-inflammatory therapy. This work describes the discovery of ITK inhibitors through structure-based design where high-resolution crystal structural information was used to optimize interactions within the kinase specificity pocket of the enzyme to improve both potency and selectivity.
Assuntos
Química Farmacêutica/métodos , Inibidores Enzimáticos/farmacologia , Proteínas Tirosina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/metabolismo , Motivos de Aminoácidos , Anti-Inflamatórios/farmacologia , Benzimidazóis/síntese química , Benzimidazóis/farmacologia , Cristalografia por Raios X/métodos , Desenho de Fármacos , Inibidores Enzimáticos/síntese química , Humanos , Concentração Inibidora 50 , Modelos Químicos , Conformação Molecular , Piridinas/química , Relação Estrutura-AtividadeRESUMO
A series of novel potent benzimidazole based inhibitors of interleukin-2 T-cell kinase (Itk) were prepared. In this report, we discuss the structure-activity relationship (SAR), selectivity, and cell-based activity for the series. We also discuss the SAR associated with an X-ray structure of one of the small-molecule inhibitors bound to ITK.
Assuntos
Amidas/química , Benzimidazóis/química , Ácidos Carboxílicos/química , Química Farmacêutica/métodos , Inibidores Enzimáticos/síntese química , Microssomos Hepáticos/metabolismo , Proteínas Tirosina Quinases/química , Animais , Benzimidazóis/síntese química , Ácidos Carboxílicos/síntese química , Cristalografia por Raios X , Desenho de Fármacos , Inibidores Enzimáticos/farmacologia , Concentração Inibidora 50 , Camundongos , Modelos Químicos , Conformação Molecular , Relação Estrutura-AtividadeRESUMO
A series of novel 12-membered ring macrolides was designed based on available information on structure-activity relationships and macrolide-ribosome interactions. Compounds with the desosamine and the anchor group properly attached to the 12-membered lactone ring exhibited improved activity against erythromycin-resistant organisms.