Lumiracoxib is a substrate-selective inhibitor of endocannabinoid oxygenation by
cyclooxygenase-2 (COX-2). We assayed a series of lumiracoxib derivatives to
identify the structural determinants of substrate-selective inhibition. The
hydrogen-bonding potential of the substituents at the ortho positions of the
aniline ring dictated the potency and substrate selectivity of the inhibitors.
The presence of a 5'-methyl group on the phenylacetic acid ring increased the
potency of molecules with a single ortho substituent. Des-fluorolumiracoxib (2)
was the most potent and selective inhibitor of endocannabinoid oxygenation. The
positioning of critical substituents in the binding site was identified from a
2.35Å crystal structure of lumiracoxib bound to COX-2.