Phospholipase A2 inhibition and atherosclerotic vascular disease: prospects for targeting secretory and lipoprotein-associated phospholipase A2 enzymes.
OBJECTIVE
Selective inhibitors of secretory phospholipase A2 and lipoprotein-associated phospholipase A2 are potential candidates for reducing recurrent cardiovascular events in patients with established coronary heart disease (CHD). With the active enrollment of CHD patients into phase III clinical trials with both classes of inhibitors, this article reviews the available experimental animal and human trial evidence that provides the rationale for the development of the phospholipase A2 inhibitors varespladib methyl and darapladib as preventive therapy.


RESULTS
Recently completed experimental animal studies, human biomarker data, and vascular imaging studies provide support for proceeding with clinical outcome trials secretory phospholipase A2 and lipoprotein-associated phospholipase A2 inhibition.


CONCLUSIONS
Both secretory phospholipase A2 and lipoprotein-associated phospholipase A2 inhibitors hold promise for the reduction of recurrent cardiovascular events in patients treated with current standards of care. The completion of the ongoing clinical event trials has the potential to provide a new dimension to secondary preventive therapy.
Rosenson
Robert S
RS
Mount Sinai School of Medicine, New York, New York, USA. robert.rosenson@mssm.edu
D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase / Q000037:antagonists & inhibitors; D000085:Acetates / Q000008:administration & dosage / Q000627:therapeutic use; D000818:Animals; D050197:Atherosclerosis / Q000188:drug therapy* / Q000201:enzymology* / Q000453:epidemiology / Q000503:physiopathology; D001547:Benzaldehydes / Q000008:administration & dosage / Q000627:therapeutic use; D015415:Biomarkers / Q000032:analysis; D018849:Controlled Clinical Trials as Topic; D004195:Disease Models, Animal; D004304:Dosage Forms; D006801:Humans; D007211:Indoles / Q000008:administration & dosage / Q000627:therapeutic use; D007651:Keto Acids; D051379:Mice; D008822:Mice, Transgenic; D058990:Molecular Targeted Therapy / Q000379:methods; D010091:Oximes / Q000008:administration & dosage / Q000627:therapeutic use; D054497:Phospholipases A2, Secretory / Q000037:antagonists & inhibitors; D012307:Risk Factors; D001713:Biphenyl Compounds; D004048:Diethylamines; D011744:Pyrimidinones; D013440:Sulfides
D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase; D000085:Acetates; D001547:Benzaldehydes; D015415:Biomarkers; D004304:Dosage Forms; D007211:Indoles; D007651:Keto Acids; D010091:Oximes; D054497:Phospholipases A2, Secretory; C545088:varespladib methyl; C529040:darapladib; D001713:Biphenyl Compounds; D004048:Diethylamines; D011744:Pyrimidinones; D013440:Sulfides