Selective COX2 inhibitors

Two compounds were identified early on as COX2 selective inhibitors, NS-398 and DuP697. Both compounds were found to share a common mechanism of isozyme selective inhibition, as detailed by Copeland et al. (1994). Here we review the results for DuP697 as an illustrative example. 

While this book was in production, Vioxx was withdrawn from the market due to unanticipated cardiovascular side effects. Whether this side effect is a specific liability of Vioxx, or a more general effect of all COX2 selective inhibitors remains unresolved at present. 

Figure 6.23 Chemical stmctures of COX2 selective inhibitors.

Structures of cyclooxygenase-2 (COX2) selective inhibitors. (A) Celecoxib and (B) Rofecoxib. 

This concept has led to market isoenzyme selective inhibitors, that is, monoamine oxidase (MAO) inhibitors (moclobemide for MAO-A as an antidepressive drug, selegiline for MAO-B in Parkinson disease), selective inhibitors for various cyclic nucleotide phosphodiesterases (sildenafil for PDE5), and selective cyclooxygenase inhibitors (celecoxib for cox2). 

Example of Scheme C When ife Is Very Small Selective COX2 Inhibitors... 

Today there are two selective COX2 inhibitors that are in clinical use for the treatment of inflammatory diseases, Vioxx1 and Celebrex. The structures of these drugs are shown in Figure 6.23 together with the structures of DuP697 and NS-398. 

The syndecan family of heparin sulfate proteoglycans (HSPGs) plays critical roles in several signal transduction pathways, and syndecan 3 intramembrane proteolysis is presenilin/y-secretase dependent (357). COX2 and COXl potentiate ABP formation through mechanisms that involve y-secretase activity. Sulindac sulfide and other NSAIDs (ibuprofen, indomethacin, R-flurbiprofen) selectively decrease the secretion of ABP independently of COX activity, probably via y-secretase inhibition (358-360). Pepstatin A methylester, sulfonamides, and benzodiazepines can also act as potent, noncompetitive, y-secretase inhibitors (335). These are but a few examples of the potential repercussions and biochemical consequences that the pharmacological manipulation of secretases in AD may bring about. 

The analysis of the crystal structures of Cox2 with a selective ligand SC-558 (PDB [66] code 1CX2) and the nonselective Coxl/Cox2 inhibitor flurbiprofen (PDB code 3PGH) fully confirms the expectedly weak match between the pharmacophore models built by variable selection and the actual Cox2 interaction map. 

Galamb, O., S. Spisak, F. Sipos, K. Toth, N. Solymosi, B. Wichmann, T. Krenacs, G. Valcz, Z. Tulassay, and B. Mokiar. 2010. Reversal of gene expression changes in the colorectal normal-adenoma pathway by NS398 selective COX2 inhibitor. Brit. ]. Cancer 102 765-73. 

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