Abstract
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.
MeSH terms
-
Administration, Oral
-
Algorithms
-
Animals
-
Anti-Inflammatory Agents, Non-Steroidal / chemical synthesis*
-
Anti-Inflammatory Agents, Non-Steroidal / pharmacokinetics
-
Anti-Inflammatory Agents, Non-Steroidal / pharmacology
-
Arthritis, Experimental / blood
-
Arthritis, Experimental / drug therapy
-
Biological Availability
-
Caco-2 Cells
-
Cell Line
-
Combinatorial Chemistry Techniques
-
Dioxanes / chemical synthesis*
-
Dioxanes / pharmacokinetics
-
Dioxanes / pharmacology
-
Enzyme Inhibitors / chemical synthesis*
-
Enzyme Inhibitors / pharmacokinetics
-
Enzyme Inhibitors / pharmacology
-
Humans
-
Imidazoles / chemical synthesis*
-
Imidazoles / chemistry
-
Imidazoles / pharmacokinetics
-
Mice
-
Mice, Inbred BALB C
-
Mitogen-Activated Protein Kinases / antagonists & inhibitors*
-
Monocytes / metabolism
-
Monte Carlo Method
-
Piperazines / chemical synthesis*
-
Piperazines / pharmacokinetics
-
Piperazines / pharmacology
-
Pyrimidines / chemical synthesis*
-
Pyrimidines / pharmacokinetics
-
Pyrimidines / pharmacology
-
Rats
-
Rats, Inbred Lew
-
Structure-Activity Relationship
-
Tumor Necrosis Factor-alpha / metabolism
-
p38 Mitogen-Activated Protein Kinases
Substances
-
2-(4-(4-fluorophenyl)-5-(2-(3-cyclopropylmethyl)pyrimidin-4-yl)-1H-imidazol-2-yl)-5-methyl-(1,3)dioxane-5-carboxylic acid 4-methylpiperazinamide
-
Anti-Inflammatory Agents, Non-Steroidal
-
Dioxanes
-
Enzyme Inhibitors
-
Imidazoles
-
Piperazines
-
Pyrimidines
-
Tumor Necrosis Factor-alpha
-
Mitogen-Activated Protein Kinases
-
p38 Mitogen-Activated Protein Kinases