Molecular Basis for Increased Cardiovascular Risk with Rofecoxib A Comparative Analysis R. Preston Mason, Ph.D. Harvard Medical School with additional scientific contributions from E.J. Corey, Ph.D. Harvard University

1
Molecular Basis for Increased Cardiovascular Risk
with RofecoxibA Comparative AnalysisR.
Preston Mason, Ph.D.Harvard Medical Schoolwith
additional scientific contributions from E.J.
Corey, Ph.D.Harvard University
2
Hypothesis

• Distinct physico-chemical properties of COX-2
  inhibitors underlie differences in their
  pharmacology, pharmacokinetics and, potentially,
  their cardiovascular safety.
• These actions may be independent of COX-2
  inhibition.

JR Vane, Science 296474 (2002)
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Mechanisms of Cardiotoxicity for Rofecoxib
Metabolite(s)
LR Reddy and EJ Corey, Tetrahedron Lett 46927
(2005)
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Rofecoxib Promotes F2-Isoprostane and Ox-LDL
through a non-Enzymatic Pathway
p lt 0.01, Drug 250 nM
p lt 0.001, Drug 100 nM
MF Walter, RP Mason Atherosclerosis 177235 (2004)
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Rofecoxib is a Pro-oxidant that Reduces the
Antioxidant Capacity of Human Plasma

• p lt 0.001

• p lt 0.0001

MF Walter, RP Mason Atherosclerosis 177235 (2004)
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Rofecoxib Alters the Structure of Lipid
Molecules X-ray Diffraction Analysis
MF Walter, RP Mason Atherosclerosis 177235 (2004)
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Rofecoxib
Reactive Metabolites
Altered lipid structure
ROS
Plasma Antioxidant Capacity
Isoprostanes
Ox-LDL
CV Risk
MF Walter, RP Mason Atherosclerosis 177235
(2004) LR Reddy and EJ Corey, Tetrahedron Lett
46927 (2005)