Varespladib (A-002), a secretory phospholipase A2 inhibitor, reduces atherosclerosis and aneurysm formation in ApoE-/- mice.
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.
Fraser
Heather
H
Anthera Pharmaceuticals Inc, San Mateo, CA, USA.
Hislop
Colin
C
Christie
Robert M
RM
Rick
Heather L
HL
Reidy
Charles A
CA
Chouinard
Michael L
ML
Eacho
Patrick I
PI
Gould
Kenneth E
KE
Trias
Joaquim
J
D000085:Acetates; D000783:Aneurysm; D000818:Animals; D001011:Aorta / Q000473:pathology; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics; D001161:Arteriosclerosis / Q000201:enzymology; D050197:Atherosclerosis / Q000201:enzymology* / Q000473:pathology*; D001798:Blood Proteins; D002784:Cholesterol; D054501:Group II Phospholipases A2; D006801:Humans; D007211:Indoles; D007651:Keto Acids; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D054497:Phospholipases A2, Secretory / Q000037:antagonists & inhibitors*
D000085:Acetates; D001057:Apolipoproteins E; D001798:Blood Proteins; D007211:Indoles; D007651:Keto Acids; C400481:PLIalpha; C117948:varespladib; D002784:Cholesterol; D054501:Group II Phospholipases A2; C516287:PLA2G2A protein, human; D054497:Phospholipases A2, Secretory; C516288:Pla2g2a protein, mouse