COX2 inhibitors

Example of Scheme C When ife Is Very Small Selective COX2 Inhibitors... 

Today there are two selective COX2 inhibitors that are in clinical use for the treatment of inflammatory diseases, Vioxx1 and Celebrex. The structures of these drugs are shown in Figure 6.23 together with the structures of DuP697 and NS-398. 

For QSAR model building purposes, the Cox2 inhibitor set was split into a learning set (LS, 80% of compounds) and a Validation set (VS, 20%). Splitting was done so as to ensure an equivalent relative distribution of actives and inactives throughout both sets, and ignoring the original provenience of the compounds. These sets were used to train and validate two types of linear QSAR approaches ... 

Unfortunately, FfipFfop and HypoGen cannot process the large training sets of the size used for QSAR model building. The set of 29 most potent Cox2 inhibitors has been submitted to HipHop and the best of the resulting hypotheses has been qualitatively compared to the overlay-based QSAR model hypothesis. 

Tab. 5.3 Correlation coefficients between the similarity-based and hypothesis-based activity prediction scores and experimental activity values, taken over the whole Cox2 inhibitor set and with...

The analysis of the crystal structures of Cox2 with a selective ligand SC-558 (PDB [66] code 1CX2) and the nonselective Coxl/Cox2 inhibitor flurbiprofen (PDB code 3PGH) fully confirms the expectedly weak match between the pharmacophore models built by variable selection and the actual Cox2 interaction map. 

Gottheb S. COX2 inhibitors may increase risk of heart attack. BMJ. 2001 323 471. 

There is also an intrinsic risk of a product being withdrawn after it has been approved for marketing. Typically this risk is at its peak in the first 3 years on the market as the number of patients in the general population exposed to the product rapidly increases and less frequent adverse events come to light. The risk of removal is, however, relatively very small and would usually be considered a normal business risk unless there is a history of failures among products of the same class. This has recently been highlighted by the discovery of an association of adverse cardiac events with COX2 inhibitors and then... 

Figure 2.131. (vida multipane) Visual inspection of a collection of small molecules, here cox2 inhibitors, is straightforward using a tiled view... 

Rocca B, Davi G. Should patients with osteoarthritis be treated with COX2 inhibitors rather than traditional NSAIDs Nat Clin Pract Rheumatol. 2007 Apr 3 [Epub ahead of print] No abstract available. Nat Clin Pract Rheumatol 2007 Apr 3 [Epub ahead of print] No abstract available 2007 4. 

Other potential uses for COX inhibitors (in particular for COX2 inhibitors) may include the treatment of Alzheimer s disease and colon cancer. In Alzheimer s dis-... 

Three structurally related COX2 inhibitors. Ranks for compounds 2 and 3 were calculated using the FT and DF methods with compound 1 as a query molecule. 

Rituximab - monoclonal antibody rheumatoid arthritis, leukaemia treatment Rofecoxib - COX2 inhibitor (withdrawn)... 

Figure 8.15 Top PDE5 inhibitors sildenafil and vardenafil. Bottom COX2 inhibitors Celebrex...

Chemists will understand that the simple change of a heterocyclic scaffold can involve completely different and often difficult synthetic routes. Those who ve tried these kinds of substitutions will also understand that most of the time such a change will result only in a massive loss of activity, and modelers will understand that it s usually difficult to say why. So no one should view any proposed heterocyclic scaffold replacement as a sure thing . That being said, apparent examples of heterocyclic core switching can also be found in the COX2 inhibitors shown in Figure 8.15 like celecoxib, valdecoxib, rofecoxib, and etoricoxib. 

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