Design of selective inhibitors of cyclooxygenase-2 as nonulcerogenic anti-inflammatory agents.

Marnett LJ, Kalgutkar AS
Curr Opin Chem Biol. 1998 2 (4): 482-90

PMID: 9736921 · DOI:10.1016/s1367-5931(98)80124-5

The discovery of a second isoform of cyclooxygenase (cyclooxygenase-2) that is expressed in inflammatory cells and the central nervous system, but not in the gastric mucosa, offers the possibility of developing anti-inflammatory and analgesic agents that lack the gastrointestinal side effects of currently available nonsteroidal anti-inflammatory drugs. Lead compounds from several different structural classes have been identified and shown to be slow, tight-binding inhibitors that express their selectivity for cyclooxygenase-2 in the time-dependent step. The determination of structures of enzyme-inhibitor co-crystals along with site-directed mutagenesis experiments reveal the molecular basis for selectivity of some, but not all, inhibitors. Preclinical and clinical studies suggest cyclooxygenase-2 inhibitors are highly promising new agents for the treatment of pain and inflammation, and for the prevention of cancer.

MeSH Terms (14)

Animals Anti-Inflammatory Agents, Non-Steroidal Cyclooxygenase 2 Cyclooxygenase 2 Inhibitors Cyclooxygenase Inhibitors Drug Design Gastrointestinal Diseases Humans Isoenzymes Membrane Proteins Models, Molecular Peroxidases Prostaglandin-Endoperoxide Synthases Ulcer

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