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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
7
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pubmed:dateCreated |
2002-3-21
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pubmed:abstractText |
In the present study we have investigated whether pharmacophore models may account for the activity and selectivity of the known cyclooxygenase-2 (COX-2) selective inhibitors of the phenylsulfonyl tricyclic series, i.e., Celecoxib (1) and Rofecoxib (3), and whether transferring this structural information onto the frame of a nonsteroidal antiinflammatory drug (NSAID), known to tightly bind the enzyme active site, may be useful for designing novel COX-2 selective inhibitors. With this aim we have developed a pharmacophore based on the geometric disposition of chemical features in the most favorable conformation of the COX-2 selective inhibitors SC-558 (2; analogue of Celecoxib (1)) and Rofecoxib (3) and the more restrained compounds 4 (DFU) and 5. The pharmacophore model contains a sulfonyl S atom, an aromatic ring (ring plane A) with a fixed position of the normal to the plane, and an additional aromatic ring (ring plane B), both rings forming a dihedral angle of 290 degrees +/- 10 degrees. The final disposition of the pharmacophoric groups parallels the geometry of the ligand SC-558 (2) in the known crystal structure of the COX-2 complex. Moreover, the nonconserved residue 523 is known to be important for COX-2 selective inhibition; thus, the crystallographic information was used to position an excluded volume in the pharmacophore, accounting for the space limits imposed by this nonconserved residue. The geometry of the final five-feature pharmacophore was found to be consistent with the crystal structure of the nonselective NSAID indomethacin (6) in the COX-2 complex. This result was used to design indomethacin analogues 8 and 9 that exhibited consistent structure-activity relationships leading to the potent and selective COX-2 inhibitor 8a. Compound 8a (LM-1685) was selected as a promising candidate for further pharmacological evaluation.
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Anti-Inflammatory Agents...,
http://linkedlifedata.com/resource/pubmed/chemical/Cyclooxygenase 1,
http://linkedlifedata.com/resource/pubmed/chemical/Cyclooxygenase 2,
http://linkedlifedata.com/resource/pubmed/chemical/Cyclooxygenase 2 Inhibitors,
http://linkedlifedata.com/resource/pubmed/chemical/Cyclooxygenase Inhibitors,
http://linkedlifedata.com/resource/pubmed/chemical/Dinoprostone,
http://linkedlifedata.com/resource/pubmed/chemical/Indomethacin,
http://linkedlifedata.com/resource/pubmed/chemical/Isoenzymes,
http://linkedlifedata.com/resource/pubmed/chemical/Lactones,
http://linkedlifedata.com/resource/pubmed/chemical/Membrane Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/PTGS1 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/PTGS2 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Prostaglandin-Endoperoxide Synthases,
http://linkedlifedata.com/resource/pubmed/chemical/Pyrazoles,
http://linkedlifedata.com/resource/pubmed/chemical/SC 558,
http://linkedlifedata.com/resource/pubmed/chemical/Sulfonamides,
http://linkedlifedata.com/resource/pubmed/chemical/Sulfones,
http://linkedlifedata.com/resource/pubmed/chemical/celecoxib,
http://linkedlifedata.com/resource/pubmed/chemical/rofecoxib
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pubmed:status |
MEDLINE
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pubmed:month |
Mar
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pubmed:issn |
0022-2623
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pubmed:author |
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pubmed:issnType |
Print
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pubmed:day |
28
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pubmed:volume |
45
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
1402-11
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pubmed:dateRevised |
2006-11-15
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pubmed:meshHeading |
pubmed-meshheading:11906281-Anti-Inflammatory Agents, Non-Steroidal,
pubmed-meshheading:11906281-Binding Sites,
pubmed-meshheading:11906281-Blood Platelets,
pubmed-meshheading:11906281-Crystallography, X-Ray,
pubmed-meshheading:11906281-Cyclooxygenase 1,
pubmed-meshheading:11906281-Cyclooxygenase 2,
pubmed-meshheading:11906281-Cyclooxygenase 2 Inhibitors,
pubmed-meshheading:11906281-Cyclooxygenase Inhibitors,
pubmed-meshheading:11906281-Dinoprostone,
pubmed-meshheading:11906281-Dose-Response Relationship, Drug,
pubmed-meshheading:11906281-Humans,
pubmed-meshheading:11906281-Indomethacin,
pubmed-meshheading:11906281-Inhibitory Concentration 50,
pubmed-meshheading:11906281-Isoenzymes,
pubmed-meshheading:11906281-Lactones,
pubmed-meshheading:11906281-Membrane Proteins,
pubmed-meshheading:11906281-Models, Chemical,
pubmed-meshheading:11906281-Models, Molecular,
pubmed-meshheading:11906281-Monocytes,
pubmed-meshheading:11906281-Prostaglandin-Endoperoxide Synthases,
pubmed-meshheading:11906281-Protein Binding,
pubmed-meshheading:11906281-Protein Conformation,
pubmed-meshheading:11906281-Pyrazoles,
pubmed-meshheading:11906281-Sulfonamides,
pubmed-meshheading:11906281-Sulfones
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pubmed:year |
2002
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pubmed:articleTitle |
Identification of novel cyclooxygenase-2 selective inhibitors using pharmacophore models.
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pubmed:affiliation |
R&D Department, Laboratorios Menarini S.A., Alfonso XII 587, 08918 Badalona, Spain. apalomer-research@ferrergrupo.com
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pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't
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