ABSTRACT
The utilization and impact of parallel synthesis on lead exploration around initial hit oxindole (1) are described. The emergent SAR, analogue design and functional impact will also be detailed.
Subject(s)
Adjuvants, Immunologic/chemistry , Protein-Tyrosine Kinases/chemistry , Protein-Tyrosine Kinases/immunology , Animals , Binding Sites , Cell Division/drug effects , Drug Design , Edema/drug therapy , Enzyme Inhibitors/chemistry , Indoles/chemistry , Inhibitory Concentration 50 , Interleukin-2/pharmacology , Janus Kinase 3 , Mice , Oxyquinoline/chemistry , Phosphorylation/drug effects , Protein Binding , Protein Structure, Tertiary , Protein-Tyrosine Kinases/metabolism , Signal Transduction/drug effects , Structure-Activity RelationshipABSTRACT
Previously we reported the identification of RPR200765A, a potent orally bioavailable pyridine-imidazole inhibitor of p38 mitogen-activated protein (MAP) kinase which suppressed paw swelling and joint pathology in streptococcal cell wall-induced arthritis. Herein, we report the use of solid-phase combinatorial organic synthesis for the parallel processing of a related pyrimidine-imidazole-based library with two points of structural variability. We report also that the application of a computer algorithm, the Monte Carlo Monomer Selection, maximized both the combinatorial synthetic efficiency and the bioavailability of the final compounds. In conjunction with the synthetic protocols, the polymer-supported quench technique was applied to the purification of the final compounds. Through rapid evaluation of the library using a p38 kinase assay and permeability assays, it was possible to identify a number of potent and orally bioavailable p38 MAP kinase inhibitors suitable for further biological investigation.
