Darapladib, a reversible lipoprotein-associated phospholipase A2 inhibitor, for the oral treatment of atherosclerosis and coronary artery disease.

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Riley RF, Corson MA

Darapladib, a reversible lipoprotein-associated phospholipase A2 inhibitor, for the oral treatment of atherosclerosis and coronary artery disease.

IDrugs. 2009 Oct;12(10):648-55.

PubMed ID

19790016 [ View in PubMed

]

Abstract

Darapladib, under development by GlaxoSmithKline plc, is a novel inhibitor of lipoprotein-associated phospholipase A2 (PLA2), an enzyme that may link lipid metabolism with inflammation, leading to the increased stability of atherosclerotic plaques present in the major arteries. Darapladib exhibits favorable pharmacokinetics, minimal predicted drug-drug interactions, sustained blood levels with once-daily oral dosing and limited inhibition of other PLA2 isozymes. Preclinical studies in diabetic-hypercholesterolemic swine (useful for the study of human atherosclerosis mechanisms) demonstrated that darapladib attenuated the progression of arterial plaques to a higher-risk phenotype by reducing the number of inflammatory macrophages within plaques and dampening T-cell responses. Two phase II clinical trials demonstrated sustained lipoprotein-associated PLA2 inhibition with daily oral dosing, and favorable effects on markers of inflammation and plaque stability. Phase III trials are ongoing to assess the safety and efficacy of darapladib in reducing adverse clinical events in patients with atherosclerosis.

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Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Darapladib	Cytosolic phospholipase A2	Protein	Humans	Unknown	Not Available	Details