Synthesis of ranolazine metabolites and their anti-myocardial ischemia activities.
The anti-anginal drug Ranolazine, a partial fatty acid oxidation (pFOX) inhibitor, is thought to modulate the metabolism during myocardial ischemia by activating pyruvate dehydrogenase activity to promote glucose oxidation. Ranolazine and its five principal metabolites: CVT-2512, CVT-2513, CVT-2514, CVT-2738 and CVT-4786, were synthesized. The effect of Ranolazine and its metabolites on the ECG (electrocardiogram) of mice with myocardial ischemia induced by isoprenaline and their effect on alleviating the symptom of myocardial ischemia were tested and compared. The results showed that CVT-2738 and CVT-2513 could be protective against mice myocardial ischemia induced by isoprenaline. Within all the metabolites tested in this study, CVT-2738 exhibited the best potency, however, it was still less potent than Ranolazine.
Yao
Zhangyu
Z
Center for Drug Discovery, College of Pharmacy, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China.
Gong
Shubo
S
Guan
Teng
T
Li
Yunman
Y
Wu
Xiaoming
X
Sun
Hongbin
H
D000083:Acetanilides / Q000138:chemical synthesis* / Q000378:metabolism / Q000627:therapeutic use*; D000818:Animals; D002317:Cardiovascular Agents; D004353:Drug Evaluation, Preclinical; D004562:Electrocardiography; D005260:Female; D005947:Glucose / Q000737:chemistry / Q000378:metabolism; D007545:Isoproterenol; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D017202:Myocardial Ischemia / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D010084:Oxidation-Reduction; D010879:Piperazines / Q000138:chemical synthesis* / Q000378:metabolism / Q000627:therapeutic use*; D000069458:Ranolazine
D000083:Acetanilides; D002317:Cardiovascular Agents; D010879:Piperazines; D000069458:Ranolazine; D005947:Glucose; D007545:Isoproterenol