Design of selective inhibitors of cyclooxygenase-2 as nonulcerogenic anti-inflammatory agents.
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.
Marnett
L J
LJ
AB Hancock Jr Memorial Laboratory for Cancer Research, Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN 37232, USA. marnett@toxicology.mc.vanderbilt.edu
Kalgutkar
A S
AS
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects / Q000737:chemistry* / Q000627:therapeutic use; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000737:chemistry* / Q000627:therapeutic use; D015195:Drug Design; D005767:Gastrointestinal Diseases / Q000139:chemically induced; D006801:Humans; D007527:Isoenzymes / Q000737:chemistry* / Q000378:metabolism; D008565:Membrane Proteins; D008958:Models, Molecular; D010544:Peroxidases / Q000737:chemistry / Q000378:metabolism; D011451:Prostaglandin-Endoperoxide Synthases / Q000737:chemistry* / Q000378:metabolism; D014456:Ulcer / Q000139:chemically induced
D000894:Anti-Inflammatory Agents, Non-Steroidal; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D008565:Membrane Proteins; D010544:Peroxidases; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases