Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
10587272 | Bioorganic & Medicinal Chemistry Letters | 2013 | 5 Pages |
Abstract
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 5â²-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 2.35Â Ã
crystal structure of lumiracoxib bound to COX-2.
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Authors
Matthew A. Windsor, Pieter L. Valk, Shu Xu, Surajit Banerjee, Lawrence J. Marnett,