Marnett Research Laboratory

Design, Synthesis, and Evaluation of Novel COX-2 Inhibitors

Cyclooxygenase-2 (COX-2) is the molecular target of non-steroidal anti-inflammatory drugs (NSAIDs) and selective COX-2 inhibitors. Our laboratory has combined structural analysis with functional studies to define the molecular determinants of the interaction of ligands (substrates and inhibitors) with COX-2. For example, we recently reported the identification of a critical H-bonding interaction that leads to the selectivity of aspirin for acetylation of Ser-530 in COX-2. Many NSAIDs are aralkyl carboxylic acids. Comparative analysis of the effect of site-directed mutation of active site residues on the binding of substrates and inhibitors to COX-1 and COX-2 led us to hypothesize that neutral derivatives of esters and amides would bind selectively to COX-2. We tested this hypothesis by synthesizing a series of neutral derivatives of NSAIDs and demonstrating increases in selectivity for COX-2 of several orders of magnitude. We are exploiting this discovery to prepare novel COX-2 inhibitors as anti-inflammatory drugs and cancer preventive agents.

Recent Leading Articles:

L.J. Marnett and R.N. DuBois "COX-2: A Target for Cancer Chemoprevention," Ann.Rev.Pharmacol.Toxicol, 42, 55-80 (2002).
[PubMed]

K.R. Kozak, J.J. Prusakiewicz, S.W. Rowlinson, and L.J. Marnett "Enantiospecific, Selective Cyclooxygenase-2 Inhibitors," Bioorg.Med.Chem.Letts, 12, 1315-1318 (2002).

C.A. Lanzo, J. Sutin, S. Rowlinson, J. Talley, and L.J. Marnett "Fluorescence Quenching Analysis of the Association and Dissociation of a Diarylheterocycle to Cyclooxygenase-1 and Cyclooxygenase-2: The Dynamic Basis of Cyclooxygenase-2 Selectivity," Biochemistry, 39, 6228-6234 (2000).

A.S. Kalgutkar, B.C. Crews, S.W. Rowlinson, A.B. Marnett, K.R. Kozak, R.P. Remmel, and L.J. Marnett "Biochemically Based Design of Cyclooxygenase-2 (COX-2) Inhibitors: Facile Conversion of Nonsteroidal Anti-inflammatory Drugs to Potent and Highly Selective COX-2 Inhibitors," Proc.Natl.Acad.Sci, 97, 925-930 (2000).

A.S. Kalgutkar, B.C. Crews, S.W. Rowlinson, C. Garner, K. Seibert, and L.J. Marnett "Aspirin-like Molecules that Covalently Inactivate Cyclooxygenase-2," Science, 280, 1268-1270 (1998).