Abstract
p38 inhibitors based on 3,4-dihydropyrido[4,3-d]pyrimidazin-2-one template were synthesized and their SAR explored. Benchmark compounds 30, 35, and 36 were found to be potent against the enzyme. Crystal structure of p38 in complex with 30 indicated a key pi-stacking interaction with the pendant tyrosine residue-35 in the glycine-rich loop.
MeSH terms
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Binding Sites
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Drug Design
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Enzyme Inhibitors / chemical synthesis*
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Enzyme Inhibitors / pharmacology*
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Glycine / chemistry
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Pyridazines / chemical synthesis*
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Pyridazines / pharmacology*
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Structure-Activity Relationship
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Tyrosine / chemistry
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p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors*
Substances
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Enzyme Inhibitors
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Pyridazines
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Tyrosine
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p38 Mitogen-Activated Protein Kinases
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Glycine