Cyclooxygenase about

Aspirin sensitive asthma, affecting about 10% of all asthmatics, is a nonallergic response to aspirin and other agents that inhibit cyclooxygenase-1. Mechanistically, the most likely reasons are lack of bronchoprotective prostaglandin E2 and shunting of arachidonic acid into the leukotriene pathway. 

Cardiotoxicity is a serious, rare adverse effect of mitox-antrone. The incidence of congestive heart failure was 0.15% in patients with normal left ventricular ejection fraction and 2.18% in those who had asymptomatic left ventricular ejection fraction of less than 50% at baseline.46 Therefore, mitoxantrone should not be used in patients with baseline cardiomyopathy, even if asymptomatic. The risk of cardiotoxicity is dose-related. The maximum lifetime dose of mitoxantrone is 140 mg/m2, or about 3 years of MS therapy. The use of cyclooxygenase-2 inhibitors should be avoided in patients receiving mitoxantrone because of a potential for worsening cardiac toxicity.46... 

The enzyme that catalyses these remarkable reactions, cyclooxygenase, is an important target for medicinal chemists. Inhibiting PG synthesis can bring about a reduction of inflammation and pain, in fact, this is how aspirin works, it was not, of course, designed to work that way and its mode of action was discovered decades after its use began. There is a price to pay for such a useful... 

Figure 2.1 Acetylsalicylic acid 1 (Aspirin , Bayer) is much more than a prodrug of salicylic acid. Its major contribution to biological activity comes from a unique mechanism of action the activated acetyl group is transferred to a serine hydroxyl group in the binding site of cyclooxygenase. Merbaphen 2 (Novasurol , Bayer) was the first example of an organomercurial diuretic some analogs with less severe side effects were the therapeutic standard from about 1920 to 1950.

While diclofenac and most other cyclooxygenase inhibitors act competitively (i.e., non-covalently), acetylsalicylic acid causes covalent modification of serine 530. Its effect may therefore last longer than that of a non-covalent inhibitor. Interestingly, the half-life of acetylsalicylic acid is rather short - about 15 minutes most of the drug is just hydrolysed to acetic acid and salicylic acid. However, salicylic acid itself still acts as a (competitive) inhibitor of Cox. Also, the covalent modification of Cox achieved early on will persist after elimination of acetylsalicylic acid, so that the clinical effect of this drug will outlast its elimination. 

Given the homology between the two cyclooxygenases, the reexamination of known anti-inflammatory agents, with particular interest in reported PGHS inhibitors, is an area of research regenerated by the identification of the inducible COX-2 isoform. Some of the most selective NSAIDs, such as diclofenac, have COX-l/COX-2 selectivities in about the threefold range (386). However, tomexiprole (86) was reported to have 30-fold COX-2 selec-... 

Because of concerns about not detecting low concentrations of active compounds in such large mixtures, the current trend is toward much smaller mixtures containing only hundreds or even dozens of compounds. For example, the Affymax group prepared a library containing mixtures of only 540 compounds and identihed potent cyclooxygenase-1 inhibitors after deconvolution (34). The issue of optimum mixture size is not yet settled and discussion will no doubt continue for some time. 

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