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rdf:type |
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lifeskim:mentions |
umls-concept:C0023621,
umls-concept:C0025664,
umls-concept:C0205531,
umls-concept:C0226896,
umls-concept:C0442027,
umls-concept:C0935763,
umls-concept:C1120843,
umls-concept:C1152564,
umls-concept:C1366876,
umls-concept:C1527415,
umls-concept:C1883254
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pubmed:issue |
11
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pubmed:dateCreated |
2002-5-16
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pubmed:abstractText |
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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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
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pubmed:status |
MEDLINE
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pubmed:month |
May
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pubmed:issn |
0022-2623
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pubmed:author |
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pubmed:issnType |
Print
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pubmed:day |
23
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pubmed:volume |
45
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
2173-84
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pubmed:dateRevised |
2009-11-19
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pubmed:meshHeading |
pubmed-meshheading:12014955-Administration, Oral,
pubmed-meshheading:12014955-Algorithms,
pubmed-meshheading:12014955-Animals,
pubmed-meshheading:12014955-Anti-Inflammatory Agents, Non-Steroidal,
pubmed-meshheading:12014955-Arthritis, Experimental,
pubmed-meshheading:12014955-Biological Availability,
pubmed-meshheading:12014955-Caco-2 Cells,
pubmed-meshheading:12014955-Cell Line,
pubmed-meshheading:12014955-Combinatorial Chemistry Techniques,
pubmed-meshheading:12014955-Dioxanes,
pubmed-meshheading:12014955-Enzyme Inhibitors,
pubmed-meshheading:12014955-Humans,
pubmed-meshheading:12014955-Imidazoles,
pubmed-meshheading:12014955-Mice,
pubmed-meshheading:12014955-Mice, Inbred BALB C,
pubmed-meshheading:12014955-Mitogen-Activated Protein Kinases,
pubmed-meshheading:12014955-Monocytes,
pubmed-meshheading:12014955-Monte Carlo Method,
pubmed-meshheading:12014955-Piperazines,
pubmed-meshheading:12014955-Pyrimidines,
pubmed-meshheading:12014955-Rats,
pubmed-meshheading:12014955-Rats, Inbred Lew,
pubmed-meshheading:12014955-Structure-Activity Relationship,
pubmed-meshheading:12014955-Tumor Necrosis Factor-alpha,
pubmed-meshheading:12014955-p38 Mitogen-Activated Protein Kinases
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pubmed:year |
2002
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pubmed:articleTitle |
An algorithm-directed two-component library synthesized via solid-phase methodology yielding potent and orally bioavailable p38 MAP kinase inhibitors.
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pubmed:affiliation |
Centre de Recherche de Paris, Aventis Pharma S.A., 94403 Vitry sur Seine CEDEX, France.
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pubmed:publicationType |
Journal Article
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