ABSTRACT
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.
Subject(s)
Anti-Inflammatory Agents/pharmacology , Protein Kinase Inhibitors/pharmacology , Pyridines/pharmacology , Skin/drug effects , Syk Kinase/antagonists & inhibitors , Administration, Topical , Anti-Inflammatory Agents/administration & dosage , Anti-Inflammatory Agents/chemical synthesis , Anti-Inflammatory Agents/chemistry , Catalytic Domain , Cell Line, Tumor , Humans , Molecular Docking Simulation , Molecular Structure , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Pyridines/administration & dosage , Pyridines/chemical synthesis , Pyridines/chemistry , Structure-Activity Relationship , Syk Kinase/chemistryABSTRACT
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
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.
Subject(s)
Benzimidazoles/pharmacology , Enzyme Inhibitors/pharmacology , Hydrolases/antagonists & inhibitors , Neutrophils/drug effects , Animals , Benzimidazoles/chemical synthesis , Binding, Competitive , Calcium/metabolism , Citrulline/metabolism , Enzyme Inhibitors/chemical synthesis , HEK293 Cells , Histones/metabolism , Humans , In Vitro Techniques , Mice , Models, Molecular , Protein-Arginine Deiminase Type 4 , Protein-Arginine Deiminases , Small Molecule Libraries , Substrate SpecificityABSTRACT
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.
