Structural basis for selective inhibition of cyclooxygenase-2 by anti-inflammatory agents

  title={Structural basis for selective inhibition of cyclooxygenase-2 by anti-inflammatory agents},
  author={Ravi G. Kurumbail and Anna M. Stevens and James K. Gierse and Joseph J. McDonald and Roderick A. Stegeman and Jina Y. Pak and Daniel Gildehaus and Julie M. iyashiro and Thomas D Penning and Karen Seibert and Peter C. Isakson and William C. Stallings},
PROSTAGLANDINSand glucocorticoids are potent mediators of inflammation. Non-steroidal anti-inflammatory drugs (NSAIDs) exert their effects by inhibition of prostaglandin production. The pharmacological target of NSAIDs is cyclooxygenase (COX, also known as PGH synthase), which catalyses the first committed step in arachidonic-acid metabolism1,2. Two isoforms of the membrane protein COX are known3: COX-1, which is constitu-tively expressed in most tissues, is responsible for the physiological… 

The structure of human cyclooxygenase-2 and selective inhibitors

A hypothesis derived from these discoveries proposes that the undesirable side effects of classical COX inhibitors results from the inhibition of COX-1, whereas the therapeutic, anti-inflammatory effects result from the inhibitedCOX-27.

Recently reported inhibitors of cyclooxygenase-2

Selective COX-2 inhibitors have been demonstrated to be anti-inflammatory and analgesic without causing the gastrointestinal damage associated with current non-selective cyclooxygenase inhibitors.

Inhibitors of cyclooxygenases: mechanisms, selectivity and uses.

  • B. Rm
  • Medicine, Biology
  • 2006
The discovery of cyclooxygenase-2 and the establishment of its structure led to the development of selective inhibitors of this enzyme, such as celecoxib and rofecoxib, with potent anti-inflammatory actions but with reduced gastrotoxic effects.

Structural diversity of selective COX-2 inhibitors

These bioactive lipids mediate numerous physiological and pathophysiological effects, including pain, fever, inflammation, hemostasis, and regulation of renal function and maintenance of mucosal integrity in the stomach.

Cyclooxygenase Isozymes: The Biology of Prostaglandin Synthesis and Inhibition

Characterization of the two COX isozymes is allowing the discrimination of the roles each play in physiological processes such as homeostatic maintenance of the gastrointestinal tract, renal function, blood clotting, embryonic implantation, parturition, pain, and fever.

Cyclooxygenase-2--10 years later.

  • B. HinzK. Brune
  • Medicine, Biology
    The Journal of pharmacology and experimental therapeutics
  • 2002
The present review assesses recent advances in COX-2 research, with particular emphasis on new insights into pathophysiological and physiological functions of this isoenzyme.

Cyclooxygenase-2 inhibitors in tumorigenesis (Part II).

  • M. Taketo
  • Medicine, Biology
    Journal of the National Cancer Institute
  • 1998
Accumulating evidence indicates that NSAIDs can reduce the incidence of colorectal cancers in human and experimental animals and can reduced the number and size of polyps in patients with familial adenomatous polyposis.

Cyclooxygenases: structural, cellular, and molecular biology.

This review examines how the structures of these enzymes relate mechanistically to cyclooxygenase and peroxidase catalysis, and how differences in the structure of PGHS-2 confer on this isozyme differential sensitivity to COX-2 inhibitors.

Cyclooxygenase inhibitors--current status and future prospects.




Pharmacological and biochemical demonstration of the role of cyclooxygenase 2 in inflammation and pain.

  • K. SeibertY. Zhang P. Isakson
  • Medicine, Biology
    Proceedings of the National Academy of Sciences of the United States of America
  • 1994
In an animal model of acute inflammation, a selective inhibitor of COX-2 inhibited edema at the inflammatory site and was analgesic but had no effect on PG production in the stomach and did not cause gastric toxicity.

Differential inhibition of human prostaglandin endoperoxide H synthases-1 and -2 by nonsteroidal anti-inflammatory drugs.

An in vitro expression system for accurate kinetic analyses of the inhibition of the human prostaglandin H synthase isozymes by nonsteroidal anti-inflammatory drugs (NSAIDs) indicates that neither measurements of affinities of NSAIDs for hPGHS-2 conducted in vitro with 10 microM arachidonate nor measurements of time-dependent inhibition of hPG HS-2 always predict whether a compound has anti- inflammatory activity in vivo.

A Single Amino Acid Difference between Cyclooxygenase-1 (COX-1) and −2 (COX-2) Reverses the Selectivity of COX-2 Specific Inhibitors*

It is indicated that the single amino acid substitution of isoleucine at position 509 for a valine is sufficient to confer COX-2 selectivity in this example of a diaryl-heterocycle COX inhibitor.

Mechanism of selective inhibition of the inducible isoform of prostaglandin G/H synthase.

Data suggest that binding of these inhibitors to COX2 induces a slow structural transition of the enzyme that results in its selective inactivation, suggesting that inhibition is not mediated by covalent modification of the enzymes.

Synthesis and use of iodinated nonsteroidal antiinflammatory drug analogs as crystallographic probes of the prostaglandin H2 synthase cyclooxygenase active site.

The preparation and characterization of novel potent iodinated analogs of the NSAIDs indomethacin and suprofen are reported, as well as the refined X-ray crystal structures of their complexes with PGHS-1.

Inducible isoforms of cyclooxygenase and nitric-oxide synthase in inflammation.

The rise in COX and NOS activities in the skin during the acute phase reinforces the proinflammatory role for prostanoids and suggests one also for nitric oxide and there may be differential regulation of these enzymes, perhaps due to the changing pattern of cytokines during the inflammatory response.

Prostaglandin endoperoxide synthases-1 and -2.