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An algorithm-directed two-component library synthesized via solid-phase methodology yielding potent and orally bioavailable p38 MAP kinase inhibitors.

Jeffrey M McKenna·Frank Halley·John E Souness·Iain M McLay·Stephen D Pickett·Alan J Collis·Kenneth Page·Imtiaz Ahmed
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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.

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Administration, OralAlgorithmsAnimalsAnti-Inflammatory Agents, Non-SteroidalArthritis, ExperimentalBiological AvailabilityCaco-2 CellsCell LineCombinatorial Chemistry TechniquesDioxanesEnzyme InhibitorsHumansImidazolesMiceMice, Inbred BALB CMitogen-Activated Protein KinasesMonocytesMonte Carlo MethodPiperazinesPyrimidinesRatsRats, Inbred LewStructure-Activity RelationshipTumor Necrosis Factor-alphap38 Mitogen-Activated Protein KinasesJournal Article

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Jeffrey M McKenna, Frank Halley, John E Souness, Iain M McLay, Stephen D Pickett, Alan J Collis, Kenneth Page, Imtiaz Ahmed. 2002-05-23. An algorithm-directed two-component library synthesized via solid-phase methodology yielding potent and orally bioavailable p38 MAP kinase inhibitors.. https://doi.org/10.1021/jm011132l

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