varespladib-methyl and darapladib

Certain members of the phospholipase A(2) superfamily of enzymes have established causal involvement in atherosclerosis, thus at least two groups of this family of enzymes have been considered potential candidates for the prevention of cardiovascular events. Recently completed experimental animal studies, human biomarker data, vascular imaging studies, and genome-wide atherosclerosis studies provide the rationale for proceeding with clinical outcome trials directed at inhibition of secretory phospholipase A(2) and lipoprotein-associated phospholipase A(2). A clinical trial with the sPLA(2) inhibitor varespladib methyl was recently terminated, while clinical trials with the Lp-PLA(2) inhibitor darapladib are being conducted in coronary heart disease patients. This article reviews the available experimental animal and human trial evidence that serve as the basis for the development of these two classes of phospholipase A(2) inhibitors.

Topics: 1-Alkyl-2-acetylglycerophosphocholine Esterase; Acetates; Animals; Atherosclerosis; Benzaldehydes; Biomarkers; Cardiovascular Diseases; Clinical Trials as Topic; Enzyme Inhibitors; Guinea Pigs; Humans; Indoles; Keto Acids; Mice; Mutation, Missense; Myocardial Ischemia; Myocytes, Cardiac; Oximes; Phospholipases A2, Secretory; Polymorphism, Genetic; Risk Factors

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.. 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.. 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.

Topics: 1-Alkyl-2-acetylglycerophosphocholine Esterase; Acetates; Animals; Atherosclerosis; Benzaldehydes; Biomarkers; Controlled Clinical Trials as Topic; Disease Models, Animal; Dosage Forms; Humans; Indoles; Keto Acids; Mice; Mice, Transgenic; Molecular Targeted Therapy; Oximes; Phospholipases A2, Secretory; Risk Factors