Preliminary studies are proposed to explore the value of an in vitro screening program to identify classes of compounds with potential as new anticoagulant drugs. Vitamin K epoxide reductase is a key enzyme in the role of vitamin K to promote blood coagulation factor synthesis, appears to be the site of action of the currently used coumarin anticoagulants, and is a suitable target enzyme for the development of new therapeutic agents. Inhibition of this enzyme results in effective vitamin K deficiency, hence cessation of coagulation factor synthesis, and decreased blood coagulability. Control of coagulation at this site has the advantage that full coagulation factor activity can be rapidly restored by doses of vitamin K in the event of hemorrhagic anticoagulant overdose. The compounds ultimately developed out of this study may avoid a number of undesirable side effects and drug potentiation interactions of the currently used coumarin derivatives which have found wide application in the treatment of a variety of cardiovascular diseases. A second result of this study will be development of a structural data bank against which compounds intended for other purposes may be checked for potential anticoagulant side effects. The proposed studies will use in vitro assay methods already developed to screen a large number of compounds as inhibitors of vitamin K epoxide reductase. Selection of the compounds to be tested will be based on an exhaustive computer assisted search of the literature to identify all compounds that have ever been associated with hemorrhagic incidents. Correlation among these compounds will identify common substructural elements which confer anticoagulant activity. Selection of compounds will be further guided by the present understanding of the enzyme and its known inhibitors to identify additional compounds possessing key structural features likely to result in inhibition. The advantage of the in vitro screeing approach is that it will identify compounds which due to their pharmacokinetic behavior may not show anticoagulant activity, but which contain subfragments of potential interest. This approach is complimentary to the """"""""rational"""""""" approach based on determination of the mechanism of the target enzyme and directed design of specific inhibitors. Information gained in this study will contribute to an understanding of the mechanism of the enzyme, which will in turn influence the selection of compounds to be tested.
| Preusch, P C; Smalley, D M (1990) Vitamin K1 2,3-epoxide and quinone reduction: mechanism and inhibition. Free Radic Res Commun 8:401-15 |
| Preusch, P C; Hazelett, S E; Lemasters, K K (1989) Sulfaquinoxaline inhibition of vitamin K epoxide and quinone reductase. Arch Biochem Biophys 269:18-24 |
| Smalley, D M; Preusch, P C (1988) Analysis of gamma-carboxyglutamic acid by reverse phase HPLC of its phenylthiocarbamyl derivative. Anal Biochem 172:241-7 |
| Hazelett, S E; Preusch, P C (1988) Tissue distribution and warfarin sensitivity of vitamin K epoxide reductase. Biochem Pharmacol 37:929-34 |
