Naproxen pharmacological activity

The enzymatic enantioselective hydrolysis of esters of naproxen and ibuprofen has attracted considerable attention because the (S)-enantiomers of these nonsteroidal anti-inflammatory drugs (NSAIDs) are the pharmacologically active isomers. These reactions have been successfully performed in a range of ionic liquids (Figure 10.10) [60, 65, 121]. 

Various arylpropionic acids show similar specificity. For most, if not all, the (5) enantiomer is the pharmacologically active one, whereas the R) enantiomer is usually much less active, although the ratio of iS)/ R) activity varies from drug to drug (and species to species). Only one of these drugs, however, is administered as the separated (S) enantiomer (naproxen, Naprosyn ). Normally these drugs are considered safe, and one cannot readily differentiate between the relative activities of the (S) and (R) forms because the in vivo half-life is very short, typically one or two hours. In patients with impaired renal function, where clearance is much slower, however, problems can arise. From in vivo studies of ibuprofen, it was established that the (S)-(-l-) isomer was responsible for antiinflammatory activity. In vivo, however, the (/ )-(-) isomer may become active because there is stereoselective inversion from R) to (S) (but not from 5 to R) in vivo with a half-life of about two hours. This inversion apparently proceeds by stereoselective formation of the coenzyme A (CoA) ester of the (f )-(-)-arylpropionic acid, followed by epimerization and release of the (S)-(+)-enantiomer. This epimerization is observed in vivo before the oxidative metabolism. Such inversion from (R) to (S) in vivo is also known for fenoprofen and benoxa-profen, and is expected to occur for most of the drugs of this series. ... 

Some NSAIDs are sold as racemic mixtures. One coimnon example is ibuprofen, sold as Advil , and marketed by Pfizer. Typically, only a single enantiomer is pharmacologically active. In the case of ibuprofen, it is the (S)-enantiomer. The inactive (R)-enantiomer in racemic ibuprofen is converted by an isomerase enzyme in the gut into the active enantiomer. Ibuprofen is now available as single enantiomer in certain preparations that supposedly has improved therapeutic value. Naproxen has always been marketed as the single enantiomer. 

Hydrocyanation of vinylarenes provides an interesting access to antiinflammatory and pain killer drugs such as naproxen and dexibuprofen (the pharmacologically active enantiomer of ibuprofen, Scheme 8.3). However, the enantioselective hydrocyanation of these substrate types remains a challenge. In 1994, RajanBabu and Casalnuovo [14] reported the application of glucophosphinite ligands 1 for the hydrocyanation of P-vinylnaphathalene 3. 

Van HA, Schwartz Jl, Depre M et al. Comparative inhibitory activity of rofecoxib, meloxicam, diclofenac, ibuprofen, and naproxen on COX-2 versus COX-1 in healthy volunteers. Journal of Clinical Pharmacology 2000 40 1109-1120. 

All compounds of the test dataset are nonsteroidal anti-inflammatory drugs (NSAIDs) and are thus relatively similar in terms of their pharmacological properties (Fig. 18). The compounds are 1, acetylsalicylic acid 2, diclofenac 3, flufe-namic acid 4, flubiprofen 5, ibuprofen 6, indometacin 7, ketoprofen 8, meclofe-namic acid 9, mefenamic acid 10, naproxen 11, piroxicam 12, sulindac sulfide (active metabolite of sulindac) 13, tenoxicam 14, meloxicam 15, cgp 28238 16, DuP-697 17, L-745-337 18, 6-methoxy-2-naphthylacetic acid (active metabolite of nabumeton) 19, NS-389 20, SC 58125. 

Celecoxib is currently indicated for the relief of signs and symptoms of osteoarthritis and rheumatoid arthritis and to reduce the number of adenomatous colorectal polyps in familial adenomatous polyposis as an adjunct to usual care. Celecoxib is at least as effective as naproxen in the symptomatic management of osteoarthritis and at least as effective as naproxen and diclofenac in the symptomatic treatment of rheumatoid arthritis, and it is less likely to cause adverse Gl effects. Celecoxib appears to be effective in the management of pain associated with both of these arthritic conditions, but effectiveness in acute or chronic pain has not been fully demonstrated. Unlike aspirin, celecoxib does not exhibit antiplatelet activity. Concomitant administration of aspirin and celecoxib may increase the incidence of Gl side effects. Another notable potential drug interaction with celecoxib is its ability, like other NSAIDs, to reduce the blood pressure response to angiotensin-converting enzyme inhibitors. A more detailed discussion of the chemical, pharmacological, pharmacokinetic, and clinical aspects of celecoxib is available (81). 

As mentioned above, ketoprofen is widely used in clinical practice as a nonsteroidal anti-inflammatory drug, like the other 2-arylpropionic acids such as naproxen and ibuprofen. The anti-inflammatory activity of ketoprofen was previously believed to reside in its (S)-enantiomer. However, research has indicated that the (f )-enantiomer of ketoprofen was able to prevent periodontal disease and was thus of pharmacological value as a toothpaste additive. It has also been discovered that (i )-ketoprofen has several previously unappreciated advantages as an analgesic and antipyretic. Another yeast strain, Citeromyces matriemis CGMCC 0573, was therefore isolated for the enantioselective hydrolysis of (i )-ketoprofen ethyl ester. ... 

NSAIDs, such as aspirin, IND, ketoprofen, ibuprofen, naproxen, sulindac and flurbiprofen, are widely used in treatment of chronic inflammatory diseases. Recent studies have also shown that they have activity in retardation of colonic tumor growth [89-91]. However, oral administration of NSAIDs usually generates gastrointestinal side effects (e.g. gastric ulcers and gastric perforation) [92]. Therefore, colon-specific and controlled release of NSAIDs are important to achieve sustained pharmacologic effects and reduce the side effects. 

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