Vitamin K is an important vitamin that mediates, by means of the vitamin K-dependent gamma-glutamyl carboxylase (GGCX), the activation of important blood clotting factors.  It is essential that the vitamin be rapidly recycled in the living organism, and this is accomplished by means of the vitamin K cycle, in which vitamin K (the naphthoquinone form, taken in as part of the diet) is first reduced by the vitamin K epoxide reductase complex 1 (VKORC1) or the NADH-dependent vitamin K quinone reductase (VKQR) to the active, (naphthohydroquinone) form.  This form of vitamin K then participates in one of the most remarkable transformations known.  The naphthohydroquinone reacts with molecular oxygen in the presence of a base strong enough to deprotonate the phenol (this is known to be a amino group in the GGCX), to give the 2,3-epoxy-1,4-naphthoquinone form (the vitamin K epoxide) of the vitamin, and a species (believed to be a strong base) that removes hydrogen from the side chains of glutamate (Glu) residues in the substrate and permits them to react with molecular carbon dioxide to give the corresponding gamma-carboxyglutamate (Gla) residues and a molecule of water.  The epoxide is then reduced by VKORC1 to the naphthoquinone form of the vitamin.


Scheme 1.  The vitamin K cycle.


Warfarin, which is an inhibitor of VKORC1, is the only oral anticoagulant currently approved by the FDA for the long-term treatment of thromboembolic disorders, but it suffers from a number of major drawbacks:  For example, it has a poor therapeutic index, its stable dosing in individuals is difficult to predict, and its inactivation by cytochromes is highly dependent on an individual's genotype.


We are working to try to develop new candidate compounds for oral anticoagulants, and we have chosen both VKORC1 and GGCX as potential targets for our compounds.  To date, we have developed a new class of compounds that potentiate the activity of warfarin by a factor of four, without exhibiting either hepatotoxicity or nephrotoxicity in rats.  The synthesis and stereochemical analysis of these compounds is a major thrust of our current research efforts.