ABSTRACT
The B(6) vitamers have been shown to display beneficial therapeutic effects in cardiovascular related disorders. The design of novel antiplatelet agents using pyridoxine as a template has led to the discovery of a class of novel cardio- and cerebro-protective agents. The present study describes the synthesis of several of these derivatives along with the antiplatelet and antiischemic activity of derivative 16.
Subject(s)
Platelet Aggregation Inhibitors/pharmacology , Platelet Aggregation/drug effects , Pyridoxine/analogs & derivatives , Pyridoxine/pharmacology , Animals , Brain Ischemia/complications , Brain Ischemia/pathology , Brain Ischemia/prevention & control , Disease Models, Animal , Humans , In Vitro Techniques , Intracranial Thrombosis/etiology , Intracranial Thrombosis/pathology , Intracranial Thrombosis/prevention & control , Male , Myocardial Infarction/etiology , Myocardial Infarction/pathology , Myocardial Infarction/prevention & control , Platelet Aggregation Inhibitors/chemical synthesis , Platelet Aggregation Inhibitors/chemistry , Pyridoxine/chemical synthesis , Pyridoxine/chemistry , Rats , Rats, Wistar , SwineABSTRACT
On the basis of previous reports that the natural cofactor pyridoxal 5'-phosphate 1 appears to display cardioprotective properties, a series of novel mimetics of this cofactor were envisioned. As pyridoxal 5'-phosphate is a natural compound and is subject to biological degradation and elimination pathways, the objective was to generate active phosphonates that are potentially less light sensitive and more stable in vivo than the parent vitamer. Several phosphonates were designed and synthesized, and in particular, compounds 10 and 14 displayed similar biological traits to natural phosphate 1 in the rat model of regional myocardial ischemia and reperfusion. A reduction in infarct size was observed in animals treated with these compounds. In an effort to identify other relevant cardioprotective models in order to potentially define structure-activity relationships, these three compounds were tested in the rat working heart model. Compounds 1, 10, and 14 were compared to dichloroacetic acid (DCA) as positive control in this model. As with DCA, compounds 1, 10, and 14 were found to induce a shift from fatty acid oxidation toward glucose oxidation.