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Varespladib (A-002), a Secretory Phospholipase A2 Inhibitor, Reduces Atherosclerosis and Aneurysm Formation in ApoE−/− Mice

Fraser, Heather PhD*; Hislop, Colin MD*; Christie, Robert M; Rick, Heather L RVT; Reidy, Charles A MS; Chouinard, Michael L MS; Eacho, Patrick I PhD; Gould, Kenneth E PhD; Trias, Joaquim PhD*

Journal of Cardiovascular Pharmacology: January 2009 - Volume 53 - Issue 1 - p 60-65
doi: 10.1097/FJC.0b013e318195bfbc
Original Article

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.

From the *Anthera Pharmaceuticals Inc, San Mateo, CA; and †Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN.

Received for publication September 9, 2008; accepted November 18, 2008.

The authors of this report were employees of Eli Lilly and Company or Anthera Pharmaceuticals Inc.

Reprints: Dr. Joaquim Trias, Anthera Pharmaceuticals Inc, 25801 Industrial Boulevard, Suite B, Hayward, CA 94545 (e-mail:

© 2009 Lippincott Williams & Wilkins, Inc.