1-Phenyl-5-pyrazolyl ureas: potent and selective p38 kinase inhibitors.
Inhibitors of the MAP kinase p38 are potentially useful for the treatment of arthritis and osteoporosis. Several 2,3-dichlorophenyl ureas were identified as small-molecule inhibitors of p38 by a combinatorial chemistry effort. Optimization for cellular potency led to the discovery of a new class of potent and selective p38 kinase inhibitors, exemplified by the 1-phenyl-5-pyrazolyl urea 7 (IC50 = 13 nM).
Dumas
J
J
Department of Chemistry Research, Bayer Research Center, West Haven, CT 06516, USA. jacques.dumas.b@bayer.com
Hatoum-Mokdad
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Sibley
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Riedl
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Scott
W J
WJ
Monahan
M K
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Lowinger
T B
TB
Brennan
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Natero
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R
Turner
T
T
Johnson
J S
JS
Schoenleber
R
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Bhargava
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Wilhelm
S M
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Housley
T J
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Ranges
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Shrikhande
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D018501:Antirheumatic Agents / Q000138:chemical synthesis / Q000737:chemistry; D020650:Combinatorial Chemistry Techniques; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006571:Heterocyclic Compounds / Q000737:chemistry; D006801:Humans; D006843:Hydrocarbons, Chlorinated / Q000737:chemistry; D020128:Inhibitory Concentration 50; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors; D010024:Osteoporosis / Q000188:drug therapy; D010671:Phenylurea Compounds / Q000138:chemical synthesis / Q000494:pharmacology; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D012995:Solubility; D013329:Structure-Activity Relationship; D014508:Urea / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases
D018501:Antirheumatic Agents; D004791:Enzyme Inhibitors; D006571:Heterocyclic Compounds; D006843:Hydrocarbons, Chlorinated; D010671:Phenylurea Compounds; D011720:Pyrazoles; D014508:Urea; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases