COX-2 inhibitors and carbonic anhydrase activity

Abstract

Purpose To compare the carbonic anhydrase inhibition (CAI) profile of selective and non-selective COX-2 inhibitors with the prototypic CAI acetazolamide (ACZ). Methods: The CO2 hydration activity of human carbonic anhydrase II (hCAII) was determined by a colorimetric method. The enzyme concentration was 5nM. Stock solutions of the inhibitors were dissolved in either ethanol or DMSO. The fraction of inhibitory activity was calculated by comparing CO2 hydration activity of the enzyme in the absence and presence of the test compounds (tested blind to the study hypothesis). Duplicate determinations were performed. Commercially available compounds purchased at the pharmacy and excipient free compounds were used. Results: The IC50 (nM) values (from the most potent CAI to least) were: ACZ, 7.5; celecoxib, 410; valdecoxib, 24800; rofecoxib > 3X10 5 and diclofenac > 3X10 5. The structural basis underlying the differences in potency is in all likelihood the pharmacophore SO2NH2, the common molecular moiety of acetazolamide, celecoxib and valdecoxib. The sulfonamide motif is absent from rofecoxib and diclofenac. Discussion: We have demonstrated an unusual inhibition binding profile for the COX-2 inhibitor celecoxib against hCAII, an isozyme with numerous physiological roles. The nanomolar CAI is linked to the pharmacophore SO2 NH2. We suggest that celecoxib may mediate some of its actions, e.g. anti-cancer effects, HCO3- modulation, by the COX-2 independent mechanism of CAI. Clinical Pharmacology & Therapeutics (2004) 75, P49–P49; doi: 10.1016/j.clpt.2003.11.185