ABSTRACT
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.
Subject(s)
Naphthyridines/pharmacology , Protein Kinase Inhibitors/pharmacology , Administration, Oral , Animals , Biological Availability , Crystallography, X-Ray , Humans , Mutagenicity Tests , Naphthyridines/administration & dosage , Naphthyridines/pharmacokinetics , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/pharmacokinetics , Rats , Structure-Activity RelationshipABSTRACT
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.
Subject(s)
Aniline Compounds/chemistry , Aniline Compounds/therapeutic use , Anti-Inflammatory Agents/chemistry , Anti-Inflammatory Agents/therapeutic use , Arthus Reaction/drug therapy , Intracellular Signaling Peptides and Proteins/antagonists & inhibitors , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/therapeutic use , Protein-Tyrosine Kinases/antagonists & inhibitors , Pyrimidines/chemistry , Pyrimidines/therapeutic use , Administration, Oral , Aniline Compounds/pharmacology , Animals , Anti-Inflammatory Agents/pharmacology , Crystallography, X-Ray , Drug Discovery , Humans , Intracellular Signaling Peptides and Proteins/metabolism , Models, Molecular , Protein Kinase Inhibitors/pharmacology , Protein-Tyrosine Kinases/metabolism , Pyrimidines/pharmacology , Rats , Structure-Activity Relationship , Syk KinaseABSTRACT
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.
Subject(s)
Dioxygenases/metabolism , Ketoglutaric Acids/metabolism , ProteomicsABSTRACT
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).