RESUMO
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 2-oxoglutarate-dependent dioxygenase target class comprises around 60 enzymes including several subfamilies with relevance to human disease, such as the prolyl hydroxylases and the Jumonji-type lysine demethylases. Current drug discovery approaches are largely based on small molecule inhibitors targeting the iron/2-oxoglutarate cofactor binding site. We have devised a chemoproteomics approach based on a combination of unselective active-site ligands tethered to beads, enabling affinity capturing of around 40 different dioxygenase enzymes from human cells. Mass-spectrometry-based quantification of bead-bound enzymes using a free-ligand competition-binding format enabled the comprehensive determination of affinities for the cosubstrate 2-oxoglutarate and for oncometabolites such as 2-hydroxyglutarate. We also profiled a set of representative drug-like inhibitor compounds. The results indicate that intracellular competition by endogenous cofactors and high active site similarity present substantial challenges for drug discovery for this target class.
Assuntos
Dioxigenases/metabolismo , Ácidos Cetoglutáricos/metabolismo , ProteômicaRESUMO
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.
Assuntos
Compostos de Anilina/química , Compostos de Anilina/uso terapêutico , Anti-Inflamatórios/química , Anti-Inflamatórios/uso terapêutico , Reação de Arthus/tratamento farmacológico , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Tirosina Quinases/antagonistas & inibidores , Pirimidinas/química , Pirimidinas/uso terapêutico , Administração Oral , Compostos de Anilina/farmacologia , Animais , Anti-Inflamatórios/farmacologia , Cristalografia por Raios X , Descoberta de Drogas , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Modelos Moleculares , Inibidores de Proteínas Quinases/farmacologia , Proteínas Tirosina Quinases/metabolismo , Pirimidinas/farmacologia , Ratos , Relação Estrutura-Atividade , Quinase SykRESUMO
A novel series of 6-aryl-pyrazolo[3,4-b]pyridines has been identified that are potent inhibitors of glycogen synthase kinase-3 (GSK-3).