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Exploring the molecular determinants of substrate-selective inhibition of cyclooxygenase-2 by lumiracoxib.

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 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.

SUBMITTER: Windsor MA

PROVIDER: S-EPMC3857387 | biostudies-literature | 2013 Nov

REPOSITORIES: biostudies-literature

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Exploring the molecular determinants of substrate-selective inhibition of cyclooxygenase-2 by lumiracoxib.

Windsor Matthew A MA Valk Pieter L PL Xu Shu S Banerjee Surajit S Marnett Lawrence J LJ

Bioorganic & medicinal chemistry letters 20130906 21

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 singl ...[more]

PMID: 24060487

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Exploring the molecular determinants of substrate-selective inhibition of cyclooxygenase-2 by lumiracoxib.

Publications

Exploring the molecular determinants of substrate-selective inhibition of cyclooxygenase-2 by lumiracoxib.

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