- Windsor MA, Valk PL, Xu S, Banerjee S, Marnett LJ. Exploring the molecular determinants of substrate-selective inhibition of cyclooxygenase-2 by lumiracoxib. Bioorganic & medicinal chemistry letters. 2013 Nov 1;23(21). 5860-4. PMID: 24060487 [PubMed].
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.
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