An algorithm-directed two-component library synthesized via solid-phase methodology yielding potent and orally bioavailable p38 MAP kinase inhibitors.
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.
McKenna
Jeffrey M
JM
Centre de Recherche de Paris, Aventis Pharma S.A., 94403 Vitry sur Seine CEDEX, France.
Halley
Frank
F
Souness
John E
JE
McLay
Iain M
IM
Pickett
Stephen D
SD
Collis
Alan J
AJ
Page
Kenneth
K
Ahmed
Imtiaz
I
D000284:Administration, Oral; D000465:Algorithms; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001169:Arthritis, Experimental / Q000097:blood / Q000188:drug therapy; D001682:Biological Availability; D018938:Caco-2 Cells; D002460:Cell Line; D020650:Combinatorial Chemistry Techniques; D004146:Dioxanes / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D051379:Mice; D008807:Mice, Inbred BALB C; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*; D009000:Monocytes / Q000378:metabolism; D009010:Monte Carlo Method; D010879:Piperazines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D011917:Rats, Inbred Lew; D013329:Structure-Activity Relationship; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases
C455800:2-(4-(4-fluorophenyl)-5-(2-(3-cyclopropylmethyl)pyrimidin-4-yl)-1H-imidazol-2-yl)-5-methyl-(1,3)dioxane-5-carboxylic acid 4-methylpiperazinamide; D000894:Anti-Inflammatory Agents, Non-Steroidal; D004146:Dioxanes; D004791:Enzyme Inhibitors; D007093:Imidazoles; D010879:Piperazines; D011743:Pyrimidines; D014409:Tumor Necrosis Factor-alpha; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases