darapladib and varespladib

The regulation of the catalytic activity of the various phospholipase A

Topics: Acetates; Animals; Benzaldehydes; Biomarkers; Cardiovascular Diseases; Drug Design; Humans; Indoles; Inflammation; Keto Acids; Oximes; Patents as Topic; Phospholipase A2 Inhibitors

Over the last 10 to 15 years, animal and human observational studies have identified elevated levels of both proinflammatory secretory phospholipase A2-IIA and lipoprotein-associated phospholipase A2 as potential risk factors for coronary heart disease. However, Mendelian randomization, a genetic tool to test causality of a biomarker, and phase III randomized controlled trials of inhibitors of theses enzymes (varespladib and darapladib) converged to indicate that elevated levels are unlikely to be themselves causal of coronary heart disease and that inhibition had little or no clinical utility. The concordance of findings from Mendelian randomization and clinical trials suggests that for these 2 drugs, and for other novel biomarkers in future, validation of potential therapeutic targets by genetic studies (such as Mendelian randomization) before embarking on costly phase III randomized controlled trials could increase efficiency and offset the high risk of drug development, thereby facilitating discovery of new therapeutics and mitigating against the exuberant costs of drug development.

Topics: 1-Alkyl-2-acetylglycerophosphocholine Esterase; Acetates; Animals; Benzaldehydes; Biomarkers; Coronary Disease; Humans; Indoles; Keto Acids; Molecular Targeted Therapy; Oximes; Phospholipase A2 Inhibitors; Phospholipases A2, Secretory; Signal Transduction; Treatment Outcome

Phospholipase A(2) (PLA(2)) are enzymes that hydrolyze the ester bond of glycerophospholipids releasing free fatty acids and lysophospholipids, including the arachidonic acid, the precursor of the eicosanoids and the inflammatory cascades. PLA(2) are present in the atherosclerotic plaques and their direct involvement in the proatherogenic inflammatory response is well documented. Epidemiological and genetic studies have demonstrated the correlation of the PLA(2) mass and enzymatic activity with the incidence of cardiovascular diseases. The potential pro-atherogenic role of PLA(2) led to the development of two small molecules, varespladib, a reversible sPLA(2) inhibitor, and darapladib, a selective Lp-PLA(2) inhibitor. Both molecules have demonstrated antiatherosclerotic properties in animal models, and positive effects on atherosclerotic plaque composition evaluated in phase 2 clinical trials. On these grounds, the results of three phase 3 studies have recently been published: the VISTA-16 study with varespladib in patients with acute coronary syndrome, and the STABILITY and SOLID-TIMI 52 studies with darapladib in patients with stable coronary heart disease and acute coronary syndrome, respectively. Unexpectedly, both studies did not demonstrate an additional protective action of PLA 2 inhibitors over the standard of care treatment with statins, antiplatelet drugs, and coronary revascularization. In the present article, the enzymatic properties and the involvement of sPLA(2) and Lp-PLA(2) in atherogenesis are reviewed, with a focus on the results of experimental studies and clinical studies with both varespladib and darapladib inhibitors.

Topics: 1-Alkyl-2-acetylglycerophosphocholine Esterase; Acetates; Acute Coronary Syndrome; Atherosclerosis; Benzaldehydes; Clinical Trials, Phase III as Topic; Coronary Artery Disease; Humans; Indoles; Keto Acids; Lipoproteins; Oximes; Phospholipase A2 Inhibitors; Phospholipases A

How to manage residual atherosclerosis risk after the statin therapy is a major concern in cardiovascular medicine. In addition to life-style modifications, new drugs against atherosclerotic and inflammatory vascular diseases are expected. In current clinical trials, phospholipase A2 inhibitors(darapladib, varespladib), RVX-208, D-4F, CETP inhibitors (anacetrapib, dalcetrapib), succinobucol are investigated. Some has been failed, but others are still promising. On molecular target basis of PAF-AH, CETP, PON, ABC transporters of A1 and G1, SR-BI, HO-1, potential benefits and side effects are discussed.

Topics: Acetates; Amides; Apolipoprotein A-I; Atherosclerosis; Benzaldehydes; Blood Proteins; Cholesterol Ester Transfer Proteins; Clinical Trials as Topic; Drug Design; Esters; Humans; Indoles; Keto Acids; Molecular Targeted Therapy; Oxazolidinones; Oximes; Probucol; Quinazolines; Quinazolinones; Sulfhydryl Compounds

The potential for phospholipases as targets for treating atherogenesis has become more prominent over the past year with the publication of the results of Phase 2 clinical trials of two inhibitors of forms of phospholipase A2: darapladib (GSK) which inhibits lipoprotein-associated phospholipase A2 and varespladib (Anthera) an inhibitor of several secreted phospholipase A2s. Although some aspects of their biology overlap, these are distinct targets with different potential for influencing atherogenesis. The background science to these two targets is discussed in this review, noting the balance of data, from human, preclinical species and in vitro that support further development of the inhibitors into Phase 3. Note is taken of another phospholipase A2 (cytosolic) which has been less fully described but for which there has been some interest.

Topics: Acetates; Animals; Atherosclerosis; Benzaldehydes; Biomarkers; Cytosol; Drug Design; Enzyme Inhibitors; Humans; Indoles; Keto Acids; Lipoproteins; Mice; Oximes; Phospholipase A2 Inhibitors; Phospholipases A2

As the role of lipids and inflammation in the genesis and progression of the atherosclerosis disease is unquestionable, novel treatment modalities that target both aspects are currently under investigation.. For a long time atherosclerosis was regarded as a lipid-driven disease, but now it is evident that it also involves the simultaneous and combined effect of inflammation and immunological pathways. The secreted PLA2s and the lipoprotein-associated phospholipase A2 (Lp-PLA2) have been associated with atherogenesis and its complications. These two enzymes produce biologically active metabolites that are involved in several phases of the atherosclerosis process.. In animal, pathological and epidemiological studies, the increased levels of these two phospholipases (i.e. PLA2s and Lp-PLA2) have been related with an increase in complex coronary lesions and increase in major cardiovascular clinical events, respectively. Therefore, inhibition of these enzymes has become the focus of research in this last decennium. Novel pharmacological inhibitors of those enzymes such as darapladib and varespladib emerge as promising therapeutical options for treating patients with coronary artery disease. Ongoing mechanistic and clinical outcome trials will further elucidate their role in this context.

Topics: 1-Alkyl-2-acetylglycerophosphocholine Esterase; Acetates; Animals; Atherosclerosis; Benzaldehydes; Blood Proteins; Humans; Indoles; Inflammation; Keto Acids; Oximes

Phase II results of the trials of two phospholipase A2 inhibitors which may be of value in the treatment of atherosclerosis and cardiovascular disease have been reported in the past year. Darapladib (GlaxoSmithKline) is an inhibitor of lipoprotein-associated phospholipase A2 and varespladib (Anthera) inhibits several forms of the secreted phospholipase A2s. Despite the apparent similarity of mechanism, which is also built into the compounds' names, the role of the two types of phospholipase in atherogenesis is very different. Evidence for this comes from a range of preclinical studies and from epidemiological data which are summarised here. These data provide a basis for the Phase II studies and support decisions to move into Phase III, a decision which in the case of darapladib has been made and studies commenced (STABILITY trial). For varespladib the FRANCIS-ACS trial in acute coronary syndrome patients is in progress.

Topics: 1-Alkyl-2-acetylglycerophosphocholine Esterase; Acetates; Animals; Atherosclerosis; Benzaldehydes; Clinical Trials, Phase II as Topic; Drug Evaluation, Preclinical; Enzyme Inhibitors; Humans; Indoles; Keto Acids; Oximes; Phospholipase A2 Inhibitors