RESUMO
The discovery and hit-to-lead exploration of a novel series of selective IKK-ß kinase inhibitors is described. The initial lead fragment 3 was identified by pharmacophore-directed virtual screening. Homology model-driven SAR exploration of the template led to potent inhibitors, such as 12, which demonstrate efficacy in cellular assays and possess encouraging developability profiles.
Assuntos
Amidas/química , Quinase I-kappa B/antagonistas & inibidores , Indóis/química , Inibidores de Proteínas Quinases/química , Administração Oral , Amidas/síntese química , Amidas/farmacocinética , Animais , Sítios de Ligação , Simulação por Computador , Avaliação Pré-Clínica de Medicamentos , Humanos , Quinase I-kappa B/metabolismo , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacocinética , Ratos , Relação Estrutura-AtividadeRESUMO
The synthesis and SAR of a novel series of IKK2 inhibitors are described. Modification around the hinge binding region of the 7-azaindole led to a series of potent and selective inhibitors with good cellular activity.
Assuntos
Química Farmacêutica/métodos , Quinase I-kappa B/antagonistas & inibidores , Indóis/síntese química , Indóis/farmacologia , Trifosfato de Adenosina/química , Sítios de Ligação , Desenho de Fármacos , Humanos , Concentração Inibidora 50 , Modelos Químicos , Modelos Moleculares , Estrutura Molecular , Ligação Proteica , Relação Estrutura-Atividade , Sulfonamidas/químicaRESUMO
The identification and progression of a potent and selective series of isoquinoline inhibitors of IkappaB kinase-beta (IKK-beta) are described. Hit-generation chemistry based on IKK-beta active-site knowledge yielded a weakly potent but tractable chemotype that was rapidly progressed into a series with robust enzyme and cellular activity and significant selectivity over IKK-alpha.
Assuntos
Descoberta de Drogas , Quinase I-kappa B/antagonistas & inibidores , Isoquinolinas/química , Isoquinolinas/farmacologia , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Humanos , Quinase I-kappa B/química , Quinase I-kappa B/metabolismo , Concentração Inibidora 50 , Isoquinolinas/metabolismo , Modelos Moleculares , Conformação Molecular , Inibidores de Proteínas Quinases/metabolismoRESUMO
A potent and selective series of 2-amino-3,5-diarylbenzamide inhibitors of IKK-alpha and IKK-beta is described. The most potent compounds are 8h, 8r and 8v, with IKK-beta inhibitory potencies of pIC(50) 7.0, 6.8 and 6.8, respectively. The series has excellent selectivity, both within the IKK family over IKK-epsilon, and across a wide variety of kinase assays. The potency of 8h in the IKK-beta enzyme assay translates to significant cellular activity (pIC(50) 5.7-6.1) in assays of functional and mechanistic relevance.
Assuntos
Benzamidas/farmacologia , Inibidores Enzimáticos/farmacologia , Quinase I-kappa B/antagonistas & inibidores , Benzamidas/química , Inibidores Enzimáticos/química , Ligação de Hidrogênio , Modelos MolecularesRESUMO
The identification and hit-to-lead exploration of a novel, potent and selective series of substituted benzimidazole-thiophene carbonitrile inhibitors of IKK-epsilon kinase is described. Compound 12e was identified with an IKK-epsilon enzyme potency of pIC(50) 7.4, and has a highly encouraging wider selectivity profile, including selectivity within the IKK kinase family.
Assuntos
Benzimidazóis/síntese química , Benzimidazóis/farmacologia , Quinase I-kappa B/antagonistas & inibidores , Nitrilas/síntese química , Nitrilas/farmacologia , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacologia , Tiofenos/síntese química , Tiofenos/farmacologia , Ligação de Hidrogênio , Cinética , Modelos Moleculares , Tiofenos/química , Difração de Raios XRESUMO
The discovery, synthesis, potential binding mode, and in vitro kinase profile of several pyrido[1',2':1,5]pyrazolo[3,4-d]pyrimidines as potent kinase inhibitors are discussed.