Abstract
A series of pyrazole inhibitors of p38 mitogen-activated protein (MAP) kinase were designed using a binding model based on the crystal structure of 1 (SC-102) bound to p38 enzyme. New chemistry using dithietanes was developed to assemble nitrogen-linked substituents at the 5-position of pyrazoles. Calculated log D was used in tandem with structure-based design to guide medicinal chemistry strategy and improve the in vivo activity of a series of molecules. The crystal structure of an optimized inhibitor, 4 (SC-806), in complex with p38 enzyme was obtained to confirm the hypothesis that the addition of a basic nitrogen to the molecule induces an interaction with Asp112 of p38 alpha. A compound identified from this series was efficacious in an animal model of rheumatic disease.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Animals
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Antirheumatic Agents / chemical synthesis*
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Antirheumatic Agents / chemistry
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Antirheumatic Agents / pharmacology
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Arthritis, Experimental / chemically induced
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Arthritis, Experimental / drug therapy
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Collagen
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Crystallography, X-Ray
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Male
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Mice
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Mice, Inbred DBA
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Models, Molecular
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Piperazines / chemical synthesis*
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Piperazines / chemistry
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Piperazines / pharmacology
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Pyrazoles / chemical synthesis*
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Pyrazoles / chemistry
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Pyrazoles / pharmacology
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Rats
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Rats, Inbred Lew
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Structure-Activity Relationship
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p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors*
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p38 Mitogen-Activated Protein Kinases / chemistry
Substances
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1-(5-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl)-4-methylpiperazine
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Antirheumatic Agents
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Piperazines
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Pyrazoles
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Collagen
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p38 Mitogen-Activated Protein Kinases