Abstract
Inhibitors of hypoxia-inducible factor 1 (HIF-1) represent promising anticancer therapeutics. We have identified a series of potent toluidinesulfonamide HIF-1 inhibitors. However, the series was threatened by a potential liability to inhibit CYP2C9 which could cause dangerous drug-drug interactions when being coadministered with other drugs. We used structure-activity data from the PubChem database to develop a topomer CoMFA model that guided the design of novel sulfonamides with high selectivity for HIF-1 over CYP2C9 inhibition.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Aryl Hydrocarbon Hydroxylases / antagonists & inhibitors*
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Aryl Hydrocarbon Hydroxylases / chemistry
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Aryl Hydrocarbon Hydroxylases / metabolism
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Cytochrome P-450 CYP2C9
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Databases, Factual
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Drug Design*
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Drug Interactions
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Humans
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Hypoxia-Inducible Factor 1 / antagonists & inhibitors*
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Hypoxia-Inducible Factor 1 / metabolism
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Ligands
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Molecular Structure
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Quantitative Structure-Activity Relationship
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Sulfonamides / chemical synthesis
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Sulfonamides / chemistry*
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Sulfonamides / pharmacology
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Toluidines / chemical synthesis
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Toluidines / chemistry*
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Toluidines / pharmacology
Substances
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Hypoxia-Inducible Factor 1
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Ligands
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Sulfonamides
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Toluidines
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CYP2C9 protein, human
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Cytochrome P-450 CYP2C9
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Aryl Hydrocarbon Hydroxylases