Varespladib (A-002), a secretory phospholipase A2 inhibitor, reduces atherosclerosis and aneurysm formation in ApoE-/- mice

• Published in: Journal of cardiovascular pharmacology Vol. 53; no. 1; p. 60
• Main Authors: Fraser, Heather, Hislop, Colin, Christie, Robert M, Rick, Heather L, Reidy, Charles A, Chouinard, Michael L, Eacho, Patrick I, Gould, Kenneth E, Trias, Joaquim
• Format: Journal Article
• Language: English
• Published: United States 01.01.2009
• Subjects: Acetates; Aneurysm; Animals; Aorta - pathology; Apolipoproteins E - deficiency; Apolipoproteins E - genetics; Arteriosclerosis - enzymology; Atherosclerosis - enzymology; Atherosclerosis - pathology; Blood Proteins; Cholesterol; Group II Phospholipases A2; Humans; Indoles; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Phospholipases A2, Secretory - antagonists & inhibitors
• ISSN: 1533-4023
• DOI: 10.1097/fjc.0b013e318195bfbc

The family of secretory phospholipase A2 (sPLA2) enzymes has been associated with inflammatory diseases and tissue injury including atherosclerosis. A-001 is a novel inhibitor of sPLA2 enzymes discovered by structure-based drug design, and A-002 is the orally bioavailable prodrug currently in clinical development. A-001 inhibited human and mouse sPLA2 group IIA, V, and X enzymes with IC50 values in the low nM range. A-002 (1 mg/kg) led to high serum levels of A-001 and inhibited PLA2 activity in transgenic mice overexpressing human sPLA2 group IIA in C57BL/6J background. In addition, the effects of A-002 on atherosclerosis in 2 ApoE mouse models were evaluated using en face analysis. (1) In a high-fat diet model, A-002 (30 and 90 mg/kg twice a day for 16 weeks) reduced aortic atherosclerosis by 50% (P < 0.05). Plasma total cholesterol was decreased (P < 0.05) by 1 month and remained lowered throughout the study. (2) In an accelerated atherosclerosis model, with angiotensin II-induced aortic lesions and aneurysms, A-002 (30 mg/kg twice a day) reduced aortic atherosclerosis by approximately 40% (P < 0.05) and attenuated aneurysm formation (P = 0.0096). Thus, A-002 was effective at significantly decreasing total cholesterol, atherogenesis, and aneurysm formation in these 2 ApoE mouse models.