Design and Synthesis of Novel Pyridoxine 5‘-Phosphonates as Potential Antiischemic Agents

• Published in: Journal of medicinal chemistry Vol. 46; no. 17; pp. 3680 - 3687
• Main Authors: Pham, Vinh, Zhang, Wenlian, Chen, Vince, Whitney, Tara, Yao, John, Froese, Doug, Friesen, Albert D, Diakur, James M, Haque, Wasim
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 14.08.2003; Amer Chemical Soc
• Subjects: Animals; Biological and medical sciences; Cardiovascular Agents - chemical synthesis; Cardiovascular Agents - chemistry; Cardiovascular Agents - pharmacology; Cardiovascular system; Chemistry, Medicinal; Coronary Stenosis - complications; Drug Stability; Fatty Acids - metabolism; Glucose - metabolism; Glycolysis; In Vitro Techniques; Lethal Dose 50; Life Sciences & Biomedicine; Light; Medical sciences; Miscellaneous; Molecular Mimicry; Myocardial Infarction - etiology; Myocardial Infarction - pathology; Myocardial Infarction - prevention & control; Myocardial Reperfusion Injury - complications; Myocardial Reperfusion Injury - pathology; Myocardial Reperfusion Injury - prevention & control; Myocardium - metabolism; Myocardium - pathology; Organophosphonates - chemical synthesis; Organophosphonates - chemistry; Organophosphonates - pharmacology; Oxidation-Reduction; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Pyridoxal Phosphate - chemistry; Rats; Rats, Sprague-Dawley; Rats, Wistar; Science & Technology; Structure-Activity Relationship; Toxicity Tests, Acute; INFARCT SIZE; PHOSPHATE; RISK-FACTORS; PHOSPHONATE; RAT; FATTY-ACID OXIDATION; 5'-PHOSPHATE; VITAMIN-B-6; ISCHEMIC-HEART-DISEASE; CORONARY-ARTERY-DISEASE; Heart; Rat; Nitrogen heterocycle; Rodentia; Cardioprotective agent; Phosphonic acids; Alcohol; Hemiacetal; Phosphorus Organic compounds; Biological activity; Pyridine derivatives; Vertebrata; Mammalia; Animal; Bicyclic compound; Fluorine Organic compounds; Antiïschemic; Chemical synthesis; Oxygen nitrogen heterocycle
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm0300678

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.