RESUMO
The discovery and lead optimisation of a novel series of SYK inhibitors is described. These were optimised for SYK potency and selectivity against Aurora B. Compounds were profiled in a human skin penetration study to identify a suitable candidate molecule for pre-clinical development. Compound 44 (GSK2646264) was selected for progression and is currently in Phase I clinical trials.
Assuntos
Anti-Inflamatórios/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Piridinas/farmacologia , Pele/efeitos dos fármacos , Quinase Syk/antagonistas & inibidores , Administração Tópica , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/química , Domínio Catalítico , Linhagem Celular Tumoral , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Piridinas/administração & dosagem , Piridinas/síntese química , Piridinas/química , Relação Estrutura-Atividade , Quinase Syk/químicaRESUMO
PAD4 has been strongly implicated in the pathogenesis of autoimmune, cardiovascular and oncological diseases through clinical genetics and gene disruption in mice. New selective PAD4 inhibitors binding a calcium-deficient form of the PAD4 enzyme have validated the critical enzymatic role of human and mouse PAD4 in both histone citrullination and neutrophil extracellular trap formation for, to our knowledge, the first time. The therapeutic potential of PAD4 inhibitors can now be explored.
Assuntos
Benzimidazóis/farmacologia , Inibidores Enzimáticos/farmacologia , Hidrolases/antagonistas & inibidores , Neutrófilos/efeitos dos fármacos , Animais , Benzimidazóis/síntese química , Ligação Competitiva , Cálcio/metabolismo , Citrulina/metabolismo , Inibidores Enzimáticos/síntese química , Células HEK293 , Histonas/metabolismo , Humanos , Técnicas In Vitro , Camundongos , Modelos Moleculares , Proteína-Arginina Desiminase do Tipo 4 , Desiminases de Arginina em Proteínas , Bibliotecas de Moléculas Pequenas , Especificidade por SubstratoRESUMO
The optimisation of the azanaphthyridine series of Spleen Tyrosine Kinase inhibitors is described. The medicinal chemistry strategy was focused on optimising the human whole blood activity whilst achieving a sufficient margin over hERG activity. A good pharmacokinetic profile was achieved by modification of the pKa. Morpholine compound 32 is a potent SYK inhibitor showing moderate selectivity, good oral bioavailability and good efficacy in the rat Arthus model but demonstrated a genotoxic potential in the Ames assay.
Assuntos
Naftiridinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Administração Oral , Animais , Disponibilidade Biológica , Cristalografia por Raios X , Humanos , Testes de Mutagenicidade , Naftiridinas/administração & dosagem , Naftiridinas/farmacocinética , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/farmacocinética , Ratos , Relação Estrutura-AtividadeRESUMO
The lead optimisation of the diaminopyrimidine carboxamide series of spleen tyrosine kinase inhibitors is described. The medicinal chemistry strategy was focused on optimising the human whole blood activity whilst achieving a sufficient margin over liability kinases and hERG activity. GSK143 is a potent and highly selective SYK inhibitor showing good efficacy in the rat Arthus model.