Structure-activity relationship
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. 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 –SO2NHCH3 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).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 maximize potency, while the 3-trifluoromethyl group provides superior selectivity and potency. 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.
In 2001, the US Food and Drug Administration (FDA) released the full results of the Pfizer and Pharmacia study which showed that they had withheld crucial data. By 2012, a federal judge unsealed "thousands of pages of internal documents and depositions" in a "long-running securities fraud case against Pfizer. "On 11 March 2009, Scott S. Reuben, former chief of acute pain at Baystate Medical Center, Springfield, Massachusetts, revealed that the data for 21 studies he had authored for the efficacy of the drug (along with others such as Vioxx) had been fabricated. The analgesic effects of the drugs had been exaggerated. Reuben was also a former paid spokesperson for Pfizer. Although from 2002 to 2007 Pfizer underwrote much of Dr. Reubens research and "many of his trials found that Celebrex and Lyrica, Pfizer drugs, were effective against postoperative pain," Pfizer was not aware of the fraudulent data. None of the retracted studies were submitted to either the US Food and Drug Administration or the European Unions regulatory agencies prior to the drugs approval. Although Pfizer issued a public statement declaring, "It is very disappointing to learn about Dr. Scott Reubens alleged actions. When we decided to support Dr. Reubens research, he worked for a credible academic medical center and appeared to be a reputable investigator", the documents unsealed in 2012, revealed that by February 2000, Pharmacia employees had devised a strategy to present the findings.