Design and synthesis of novel pyridoxine 5'-phosphonates as potential antiischemic agents.
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.
Pham
Vinh
V
Medicure Inc. and CanamBioresearch Inc., 6-1200 Waverley Street, Winnipeg, Manitoba, Canada, R3T 0P4.
Zhang
Wenlian
W
Chen
Vince
V
Whitney
Tara
T
Yao
John
J
Froese
Doug
D
Friesen
Albert D
AD
Diakur
James M
JM
Haque
Wasim
W
D000818:Animals; D002317:Cardiovascular Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D023921:Coronary Stenosis / Q000150:complications; D004355:Drug Stability; D005227:Fatty Acids / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D006019:Glycolysis; D066298:In Vitro Techniques; D007928:Lethal Dose 50; D008027:Light; D018716:Molecular Mimicry; D009203:Myocardial Infarction / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D015428:Myocardial Reperfusion Injury / Q000150:complications / Q000473:pathology / Q000517:prevention & control*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D063065:Organophosphonates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010084:Oxidation-Reduction; D011732:Pyridoxal Phosphate / Q000737:chemistry*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D013329:Structure-Activity Relationship; D023382:Toxicity Tests, Acute
D002317:Cardiovascular Agents; D005227:Fatty Acids; D063065:Organophosphonates; D011732:Pyridoxal Phosphate; D005947:Glucose