Abstract
An anti-inflammatory 1,2,4-phenylenetriamine-containing series of FMS inhibitors with a potential to form reactive metabolites was transformed into a series with equivalent potency by incorporation of carbon-based replacement groups. Structure-based modeling provided the framework to efficiently effect this transformation and restore potencies to previous levels. This optimization removed a risk factor for potential idiosyncratic drug reactions.
MeSH terms
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Anti-Inflammatory Agents / chemical synthesis
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Anti-Inflammatory Agents / chemistry
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Anti-Inflammatory Agents / pharmacology*
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Computer Simulation
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Dose-Response Relationship, Drug
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Drug Design*
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Drug Evaluation, Preclinical
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Enzyme Inhibitors / chemical synthesis
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Enzyme Inhibitors / chemistry
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Enzyme Inhibitors / pharmacology*
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Hydrogen Bonding
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Inhibitory Concentration 50
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Models, Molecular
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Molecular Structure
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Phenylenediamines / chemical synthesis
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Phenylenediamines / chemistry
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Phenylenediamines / pharmacology*
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Receptor, Macrophage Colony-Stimulating Factor / antagonists & inhibitors*
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Stereoisomerism
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Structure-Activity Relationship
Substances
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Anti-Inflammatory Agents
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Enzyme Inhibitors
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Phenylenediamines
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Receptor, Macrophage Colony-Stimulating Factor