Title: Busting Blood Clots with Safer Anticoagulants
1Busting Blood Clots with Safer Anticoagulants
- David E. Lewis a and Michael D. Caldwell b
- a Department of Chemistry, UW-Eau Claire
- b Department of Surgery, Marshfield Clinic
2What is it that a synthetic organic chemist who
nearly failed biology could possibly have in
common with a vascular surgeon of the first rank?
or..
3Vitamin K and Blood Coagulation!
- The prevention of thromboses is an important
problem in a large number of patients (Over 30
million prescriptions for oral anticoagulants
annually) - The chemistry and mechanism of vitamin K presents
a chemically interesting challenge - The factors affecting the efficacy of warfarin,
the benchmark oral anticoagulant are still not
completely understood - There is a place for new, safer oral
anticoagulants (Warfarin, 2nd in list of drugs
with greatest ADE)
4Blood ClottingThe Vitamin K Cycle
- Modulated by the vitamin K-dependent
?-carboxylase - GGCX carboxylates Glu residues to Gla residues
using molecular oxygen and carbon dioxide - Vitamin K is regenerated in the vitamin K cycle
- VKORC-1 reduces vitamin K and its epoxide (KO) to
the dihydro form (KH2) with a sulfhydryl cofactor - VKQR reduces vitamin K to KH2 with NAD(P)H as
cofactor - A pool of vitamin K is essential to proper blood
coagulation
5Warfarin - The Benchmark Oral Anticoagulant
- Patent application by Stahmann, Ikawa and Link
in 1945 (U.S. Patent No. 2,427,578 September 16,
1947) - Patent assigned to WARF by inventors
- Name warf-(WARF) (coum)-arin
- Sodium salt is marketed as Coumadin
- S enantiomer is much more effective
6(No Transcript)
7And the Chemical Version
8How do the Structures of KO and Warfarin Compare?
9Historical Approach to Warfarin Dosing
- Marked individual dose variability
- Narrow therapeutic index
- No tests available for dosing guidelines
- Age
- BMI
- Co-morbidities
- Medications
10Large ethnic variation in warfarin doses for
stable INR (median 2.5)
Median 3.0 mg/d 5.4 mg/d 4.5
mg/d
11Wadelius M. Human Genetics 200712123
12The Fate of Warfarin Oxidation by Cytochromes
- Inhibits VKORC-1
- Effective oral anticoagulant
- Does not inhibit VKORC-1
- Not an oral anticoagulant
13Predicting the Stable Dose of Warfarin
14Our Goals
- To develop new oral anticoagulants that are more
predictable in their physiological effect than
warfarin - To develop new oral anticoagulants that are more
resistant to cytochrome oxidation than warfarin - To use the Marshfield Clinic human genomic
database to develop new oral anticoagulants whose
physiological effects are less variable over a
wider range of genomic populations
15The Division of Labor
- David E. Lewis
- Interpretation of chemical problems
- Design of new molecules for testing
- Synthesis of new candidate molecules
- Ultimately design and synthesis of combinatorial
libraries
- Michael D. Caldwell
- Development of in vitro and in vivo testing
models - Testing of new molecules as anticoagulants
- Quantitating biological testing results
16The Joint Tasks
- Interpretation of results of biological testing
- Developing SAR considerations in tested compounds
- Developing projected direction of design of next
generation of compounds
17Warfarin
Made in Wisconsin
Made Safer in Wisconsin