Abstract
The relative binding affinities to human dihydrofolate reductase of four new potential antifolates, containing ester linkages between the two aromatic systems, were estimated by free energy perturbation simulations. The ester analogue, predicted to exhibit the highest binding affinity to human dihydrofolate reductase, and a reference ester (more structurally related to methotrexate) were synthesized. As deduced from the measured IC(50) values, the calculated ranking of the ligands was correct although a greater difference in affinity was indicated by the experimental measurements. Among the new antifolates the most potent inhibitor exhibited a similar pharmacokinetic profile to methotrexate but lacked activity in a complex antiarthritic model in rat in vivo.
Publication types
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Research Support, Non-U.S. Gov't
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 / drug therapy
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Biological Availability
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Female
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Folic Acid Antagonists / chemical synthesis
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Folic Acid Antagonists / chemistry
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Folic Acid Antagonists / metabolism*
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Folic Acid Antagonists / pharmacology
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Humans
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Male
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Methotrexate / analogs & derivatives*
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Methotrexate / chemical synthesis
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Methotrexate / chemistry
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Methotrexate / metabolism*
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Models, Biological
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Models, Molecular
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Protein Binding
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Rats
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Tetrahydrofolate Dehydrogenase / chemistry
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Tetrahydrofolate Dehydrogenase / metabolism*
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Thermodynamics
Substances
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Antirheumatic Agents
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Folic Acid Antagonists
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Tetrahydrofolate Dehydrogenase
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Methotrexate