COX Inhibitors

COX-1 is constitutive, that is, always present and active it contributes to the physiological function of organs. Inhibition inevitably produces unwanted effects, such as mucosal injury, renal damage, hemodynamic changes, and disturbances of uterine function. 

COX-2 is induced by inflammatory processes and produces prostaglandins that sensitize nociceptors, evoke fever, and promote inflammation by causing vasodilation and an increase in vascular permeability. However, in some organs, COX-2 is also expressed con-stitutively (kidney, vascular endothelium, uterus, and CNS). 

Nonselective COX inhibitors derive from salicylic acid. The majority are carbonic acids, such as ibuprofen, naproxene, diclofenac, indometacin, and many more or enolic acids, such as azapropazone and meloxicam. All these drugs inhibit both COX enzymes. 

The molecules of COX-1 and COX-2 reveal a pharmacologically important difference the enzymatic pore width of COX-2 exceeds that of COX-1. The nonselective COX inhibitors can also enter the narrower pores and thus inhibit both cyclooxygenases. 

Coxibs available at present include cele-coxib (daily dosage 200-400 mg), valdecoxib (10-20 mg) (no longer available in the US) and its prodrug parecoxib (40 mg i.v.l). 

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COX-2 selectivity was evaluated in vitro by using the human whole blood assays of COX isoenzyme activity. Three compounds, not bearing the sulfonamide group present in valdecoxib, have been found to be selective COX-1 inhibitors. 

The discovery of two cyclooxygenase isoforms (COX-1 and COX-2) led to the concept that the constitutive COX-1 isoform tends to be homeostatic in function, while COX-2 is induced during inflammation and tends to facilitate the inflammatory response. On this basis, highly selective COX-2 inhibitors have been developed and marketed on the assumption that such selective inhibitors would be safer than nonselective COX-1 inhibitors but without loss of efficacy. 

The well known, beneficial influence of non-steroidal anti-inflammatory drugs (NSAID) on the progress of Alzheimer s disease has been confirmed for some NSAID subtypes. The work by Weggen et al. indicates the potential of COX 1 inhibitors (e.g. Diclofenac, Sulindac, Indomethacin, Ibuprofen, but not the most prominent, Aspirin) in PS inhibition [17]. 

Dihydroxy-4-methylcoumarin was the most potent COX-1 inhibitor, however without 5-LOX activity. The only dual inhibitor was 7,8-Dihydroxycoumarin (Daphnetin) with moderate and equal potency against both pathways [174]. 

These results demonstrate that the side pocket of COX-1, which has been considered sterically inaccessible, can bind certain (5)-hydroxyethylamide derivatives of INDO. This study also offers insight into the selective binding of amide derivatives of INDO to COX-2. It seems that the amides associate with COX-1 and COX-2 but only bind tightly to COX-2. If all INDO-amides adopt a conformation in both enzymes analogous to that of the (i )-hydroxyethylamide 8, then this complex is only stable in COX-2. Because the orientation of Arg-120 is altered in the COX-1-compound 8 complex relative to other COX-1 inhibitor complexes, it may be that COX-2 can better accommodate this conformation than COX-1. It will be interesting to test this hypothesis and to identify the protein determinants responsible for the differential stability. 

Unlike aspirin, this compound is reported to selectively acetylate the COX-2 serine residue and selectively inactivate COX-2. The I bulky heptynyl side-chain was optimized for I CCX2 selectivity in this SAR study and the I selective inhibition reported must be related I to the differences in active site or binding I pocket size, similar to the strategy for creating mary other selective inhibitors from modifica-I tions cf COX-1 inhibitors. 

Kinetics of inhibition by NSAIDs Immediate, competitive inhibition (strong for COX-1 inhibitors, weak for COX-2 inhibitors) COX-2 inhibitors noncompetitive (irreversible ), time-dependent COX-1 inhibitors competitive, immediate... 

Three 4-thiazolidinone libraries were prepared and assayed for inhibition of the enzyme cyclooxygenase-1 (COX-1), a key enzyme in the conversion of arachidonic acid to prostaglandins [421, 422], From the carboxylic acid, ester and carboxamides libraries only the methyl ester library showed significant activity. A series of three rounds of testing and deconvolution led to a compound (library 37 IC50 3.7 fiM) with equivalent in vitro activity to the commercially available COX-1 inhibitors ibuprofen and phenylbutazone. 

In addition to skin eruptions aspirin can cause a syndrome referred to as aspirin exacerbated respiratory disease (AERD) in which the classic triad of asthma, rhinitis, and aspirin sensitivity was first described by Sam ter. It is important to note that AERD has as its precursor an underlying respiratory disease such as asthma that is exacerbated by aspirin but not caused by aspirin. Briefly, the natural history of this disease indicates that the patient first develops an upper respiratory tract inflammation that persists rather than subsides. Sinusitis develops, which progresses to pansinusitis with nasal polyps and asthma noted. At some point the patient takes aspirin or some other COX-1 inhibitor and an AERD reaction occurs. Although this is truly an idiopathic reaction to NSAIDs, adult patients with chronic sinusitis and nasal polyps should be observed carefully for the potential development of AERD. 

The thermodynamically more stable lithium enolate of phenylacetone, regioselectively prepared in situ with lithium diisopropylamide (LDA) at 0 °C, reacted with arylnitrile oxides giving 5-hydroxy-2-isoxazolines 19. The adducts were dehydrated under basic conditions to afford 3-aryl-5-methyl-4-phenylisoxazoles 20 in 38-73% overall yields. The phenyl and 5-chloro-2-furyl derivatives 20 are selective cyclooxygenase-1 (COX-1) inhibitors <04JMC4881>. 

Aspirin irreversibly blocks the production of thromboxane A2 by binding to cyclo-oxygenase (COX-1) in platelets, and so inhibits platelet aggregation. The beneficial cardiovascular effects are attributed to this effect. Other NSAIDs that are COX-1 inhibitors also have this effect, but it is more short-lived since they bind reversibly. These NSAIDs can therefore competitively inhibit the binding of aspirin to platelets (a fact that was shown in vitro as early as the 1980s ). When these NSAIDs are present in sufficient quantities when a daily low-dose of aspirin is given, they therefore reduce its antiplatelet effect. In vitro study confirms that COX-2 selective NSAIDs have less effect. ... 

Abnormalities in the lipoxygenase pathway may exist in patients hypersensitive to COX-1 inhibitors since they show higher levels of leukotrienes even before exposure to aspirin and other NSAIDs. Patients with aspirin-induced asthma may show increased baseline levels of urinary UK, that increase after challenge with aspirin and correlate with the severity of the induced reaction. 

Proceeding from the observation that aspirin specifically triggers the release of 15-hydroxyeicosatetraenoic acid (15-HETE) (Fig. 9.3 Sect. 3.2.5.2 and Fig. 3.8) from epithelial cells of nasal polyps and peripheral blood leukocytes from patients with aspirin-induced asthma/rhinosinusitis, 15-HETE generation was utilized as a test for the identification of aspirin-sensitive patients. Stimulation in vitro of peripheral blood leukocytes with 200 pM of aspirin resulted in a mean increase of over 400 % in 15-HETE generation but only small to insignificant responses were seen in aspirin-tolerant asthmatic and control subjects. Sensitivity of the test was 83 % and specificity 82 % positive and negative predictive values were 0.79 and 0.86, respectively. The NSAID COX-1 inhibitor naproxen also triggered 15-HETE release but COX-2-selective NSAIDs did not. 

Patients who experience exacerbation of then-asthma after taking aspirin or other NSAID COX-1 inhibitors should avoid these drugs as well as drugs that increase leukotriene levels and topical or systemic corticosteroids. NSAIDs that have only weak inhibitory activity for the ultimate synthesis of prostaglandins such as acetaminophen and selective COX-2 inhibitors seem to be tolerated by most patients with aspirin-induced... 

In addition to the gastric, renal, and antiplatelet side effects of ketorolac, other adverse effects of ketorolac have been reported. Ketorolac, like other COX-1 inhibitors, can produce bronchoconstriction in asthmatic patients and in patients with complete or partial syndromes of nasal polyps, angioedema, and allergic reactions to NSAIDs. 

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