Tomoxiprole

The beneficial actions of nonsteroid anti-inflammatory drugs (NSAID) can be associated with inhibition of cyclo-oxygenase (COX)-2 whereas their harmful side effects are associated with inhibition of COX-1. Here we report data from two related assay systems, the human whole blood assay and a modified human whole blood assay (using human A549 cells as a source of COX-2). This assay we refer to as the William Harvey Modified Assay. Our aim was to make meaningful comparisons of both classical NSAIDs and newer COX-2-selective compounds. These comparisons of the actions of >40 NSAIDs and novel COX-2-selective agents, including celecoxib, rofecoxib and diisopropyl fluorophosphate, demonstrate a distribution of compound selectivities toward COX-1 that aligns with the risk of serious gastrointestinal complications. In conclusion, this full in vitro analysis of COX-1/2 selectivities in human tissues clearly supports the theory that inhibition of COX-1 underlies the gastrointestinal toxicity of NSAIDs in man.

Tomoxiprole is a nonsteroidal anti-inflammatory compound that was reported to have low ulcerogenic potential, a quality that would be expected of a cyclooxygenase-2-selective inhibitor, and, in fact, we find it is selective for this isozyme. In stably transfected COS cells, the compound inhibits recombinant human cyclooxygenase-2 (IC50 = 7 nM) more potently than recombinant cyclooxygenase-1 (IC50 = 240 nM), and similar results are obtained with partially pure ovine enzyme preparations. The compound is thus a very potent as well as selective inhibitor of cyclooxygenase-2. As is true of some other cyclooxygenase-2-selective inhibitors, tomoxiprole inhibition of cyclooxygenase-2 but not cyclooxygenase-1 is time-dependent.