Editing Celecoxib (section)

==Structure-activity relationship==
[[File:Monosubstituted 1,5-diarylpyrazoles.jpg|400px|right]]
[[File:Enzyme data for monosubstituted 5-aryl analogs.jpg|400px|right]]
[[File:Enzyme data for 4-substituted analogs.jpg|400px|right]]
[[File:In vitro cox-I and cox-II enzyme data for disubstituted 5-aryl analogs.jpg|400px|right]]

The Searle research group found the two appropriately substituted aromatic rings must reside on adjacent positions about the central ring for adequate COX-2 inhibition. Various modifications can be made to the 1,5-diarylpyrazole moiety to deduce the structure-activity relationship of celecoxib.<ref name="Penning">{{cite journal | vauthors = Penning TD, Talley JJ, Bertenshaw SR, Carter JS, Collins PW, Docter S, Graneto MJ, Lee LF, Malecha JW, Miyashiro JM, Rogers RS, Rogier DJ, Yu SS, Burton EG, Cogburn JN, Gregory SA, Koboldt CM, Perkins WE, Seibert K, Veenhuizen AW, Zhang YY, Isakson PC | title = Synthesis and biological evaluation of the 1,5-diarylpyrazole class of cyclooxygenase-2 inhibitors: identification of 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benze nesulfonamide (SC-58635, celecoxib) | journal = Journal of Medicinal Chemistry | volume = 40 | issue = 9 | pages = 1347–65 | date = April 1997 | pmid = 9135032 | doi = 10.1021/jm960803q }}</ref> A para-sulfamoylphenyl at position 1 of the pyrazole was found to have a higher potency for COX-2 selective inhibition than a para-methoxyphenyl (see structures 1 and 2, below). In addition, a 4-(methylsulfonyl)phenyl or 4-sulfamoylphenyl is known to be necessary for COX-2 inhibition. For instance, replacing either of these entities with a –SO<sub>2</sub>NHCH<sub>3</sub> substituent diminishes COX-2 inhibitory activity as noted with a very high inhibitory concentration-50 (see structures 3 – 5). At the 3-position of the pyrazole, a trifluoromethyl or difluoromethyl provides superior selectivity and potency compared to a fluoromethyl or methyl substitution (see structures 6 – 9).<ref name="Penning"/>

Celecoxib is compound 22; the 4-sulfamoylphenyl on the 1-pyrazol substituent is required for COX-2 inhibition and the 4-methyl on the 5-pyrazol system has low steric hindrance to maximising potency, while the 3-trifluoromethyl group provides superior selectivity and potency.<ref name="Penning" /> To explain the selectivity of celecoxib, it is necessary to analyze the free energy of binding difference between the drug molecule and COX-1 compared to COX-2 enzymes. The structural modifications highlight the importance of binding to residue 523 in the side binding pocket of the cyclooxygenase enzyme, which is an isoleucine in COX-1 and a valine in COX-2.<ref name="Price">{{cite journal | vauthors = Price ML, Jorgensen WL | title = Rationale for the observed COX-2/COX-1 selectivity of celecoxib from Monte Carlo simulations | journal = Bioorganic & Medicinal Chemistry Letters | volume = 11 | issue = 12 | pages = 1541–4 | date = June 2001 | pmid = 11412976 | doi = 10.1016/s0960-894x(00)00522-9 }}</ref> This mutation appears to contribute to COX-2 selectivity by creating steric hindrance between the sulfonamide oxygen and the methyl group of Ile523 that effectively destabilizes the celecoxib-COX-1 complex.<ref name="Price"/>