Abstract
p38 inhibitors based on 3,4-dihydropyrimido[4,5-d]pyrimidin-2-one and 3,4-dihydropyrido[4,3-d]pyrimidin-2-one platforms were synthesized and preliminary SAR explored. Among the pyrimido-pyrimidones the emergence of two sub-types of analogs-C7-amino-pyrimidines such as 24 and C7-amino-piperidines such as 42-characterized with good p38 inhibition and better off-target profiles in terms of ion channel activities was significant. Representative compound 54 in the pyrido-pyrimidone class was found to be equipotent with corresponding analog in the quinazolinone series.
MeSH terms
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Chemistry, Pharmaceutical / methods
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Drug Design
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Enzyme Inhibitors / chemistry*
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Enzyme Inhibitors / metabolism
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Enzyme Inhibitors / pharmacology
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Humans
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Inhibitory Concentration 50
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Models, Chemical
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Pyridazines / chemistry*
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Pyridazines / pharmacology
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Pyridines / chemistry
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Pyrimidines / chemistry*
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Pyrimidines / pharmacology
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Pyrimidinones / chemistry*
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Pyrimidinones / pharmacology
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Quinazolines / chemistry
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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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3,4-dihydropyridopyrimidin-2(1H)-one
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Enzyme Inhibitors
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Pyridazines
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Pyridines
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Pyrimidines
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Pyrimidinones
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Quinazolines
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p38 Mitogen-Activated Protein Kinases
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VX-745