A 24‐week Study to Evaluate the Effect of Rilapladib on Cognition and CSF Markers of Alzheimer's Disease

Small-molecule inhibitors as potential therapeutics and as tools to understand the role of phospholipases A2

“…5), which have both entered into clinical trials as potential treatment of Alzheimer's disease (AD). Rilapladib has completed a phase ΙΙa study [121] to evaluate its effect in AD, where it demonstrated improved cognitive outcomes and changes to a number of mechanism-and disease-related biomarkers, suggesting that rilapladib and inhibition of LpPLA 2 may have the potential to slow the progression of AD and alter the underlying pathology in a subpopulation of AD patients with neuroimaging evidence of cerebrovascular disease [122]. GSK2647544 has been evaluated as for the safety, tolerability, pharmacokinetics and pharmacodynamics in healthy volunteers in phase 1 clinical trials [123].…”

Investigation of a Bicyclo[1.1.1]pentane as a Phenyl Replacement within an LpPLA2 Inhibitor

“…Lipoprotein-associated phospholipase A2 (LpPLA 2 ) or platelet-activating factor acetylhydrolase (PAF-AH) has been extensively studied as a potential therapeutic target for the treatment of atherosclerosis − and more recently in other diseases where vascular inflammation may play a role, e.g., diabetic macular edema and Alzheimer’s disease. , A range of epidemiological and genetic evidence suggests that increased LpPLA 2 concentration increases the risk of myocardial infarction (MI), ischemic stroke, and cardiac death in patients with stable cardiovascular disease (CVD). ,− With considerable support for the hypothesis that LpPLA 2 is associated with atherosclerosis, a range of inhibitors has been developed, with darapladib 1 − and rilapladib 2 being well studied examples as both compounds have entered clinical trials (Figure ).…”

Evaluation of the safety, pharmacokinetics, pharmacodynamics, and drug-drug interaction potential of GSK2647544 in healthy volunteers

“…Preliminary clinical evidence that targeting Lp-PLA2 may provide a novel treatment to slow the progression of AD comes from a phase 2a study with a non-central nervous system (CNS)-penetrant Lp-PLA2 inhibitor rilapladib, which demonstrated improved cognitive outcomes and changes to a number of mechanism- and disease-related biomarkers [ 4 ]. This study was based on findings from a diabetic mellitus (DM) and hypercholesterolemic (HC) pig model, in which treatment with darapladib (another Lp-PLA2 inhibitor) numerically reduced the extent of immunoglobulin-G brain parenchyma penetration suggesting a reduction in blood brain barrier leakage, and significantly lowered the total amount of brain amyloid-β peptide 1-42 deposition compared with untreated DM/HC pigs [ 5 ].…”

“…Evidence indicates that Lp-PLA2 is also present in the human central nervous system (CNS) [ 4 ] and that its specific activity can be detected in cerebrospinal fluid [ 5 , 6 ]. Immunohistochemical evidence indicates that its expression is primarily associated with microglia [GSK data on file].…”