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Warfarin: history, tautomerism and activity
1Global Pharmaceutics and Life Cycle Technology, Dept. R43D, Bldg. AP31, Abbott Laboratories, 200 Abbott Park Road, Abbott Park, IL 60064, USA. william.r.porter@abbott.com
Journal of Computer-Aided Molecular Design
|March 31, 2010
Summary
Warfarin exists in many forms, but current software only identifies 11. This study explores warfarin tautomerism, impacting its biological and chemical properties.
Area of Science:
- Medicinal Chemistry
- Computational Chemistry
- Pharmacology
Background:
- Warfarin, a widely used anticoagulant, is administered as a racemate.
- The drug can exist in numerous distinct tautomeric forms in solution.
- Understanding these forms is crucial for predicting drug behavior.
Purpose of the Study:
- To review the history and implications of warfarin tautomerism.
- To investigate the impact of tautomerism on warfarin's biological and chemical properties.
- To present experimental and computational findings on warfarin tautomeric forms.
Main Methods:
- Literature review on warfarin tautomerism studies.
- Computational analysis using selected software to identify tautomeric forms.
- Assessment of octanol-water partition coefficients and ionization constants for different forms.
- Presentation of experimental approaches for studying tautomerism.
Main Results:
- Warfarin can exist in up to 40 distinct tautomeric forms.
- Common computational software can only distinguish 11 forms per enantiomer.
- Tautomerism significantly influences warfarin's activity, protein binding, metabolism, log P, log D, and pKa.
Conclusions:
- Warfarin's complex tautomerism presents challenges for accurate computational prediction.
- Further research is needed to fully characterize all tautomeric forms and their biological relevance.
- Accurate assessment of warfarin tautomers is essential for drug development and personalized medicine.
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