Lumiracoxib

Lumiracoxib, which has been approved in the UK but not by the FDA, has a phenyl acetic acid structure resembling diclofenac rather than the other coxibs... 

It follows that drugs that selectively inhibit COX-2 should cause fewer side effects than those that inhibit both COX-1 and COX-2. At therapeutic doses, all currently available NSAIDs, with the excqrtion of celecoxib, etoricoxib, lumiracoxib and parecoxib (the prodrug of valdecoxib), are non-selective and inhibit both COX isoforms. 

The development of the COXIBs has been based on the hypothesis COX-1 is the physiological COX and COX-2, the pathophysiological isoenzyme. Inhibition of the pathophysiological COX-2 only is assumed to result in fewer side effects as compared to non-selective inhibition of both COX isoenzymes (Fig. 2). Celecoxib, etoricoxib and lumiracoxib (in some countries also parecoxib) are the only COXIBs currently approved. 

Highly selective COX-2 inhibitors - coxibs (rofecoxib, celecoxib, or less popular - valdecoxib, etoricoxib parecoxiband lumiracoxib) - were found to be well tolerated in a series of placebo-controlled clinical trials [8]. However, rofecoxib and valdecoxib have been withdrawn from the market because of an increased incidence... 

Indomethacin and sulindac are slightly selective for COX-1. Meclofenamate and ibuprofen are approximately equipotent on COX-1 and COX-2, whereas celecoxib = diclofenac < rofecoxib = lumiracoxib < etoricoxib in inhibition of COX-2 (listed in order of increasing average selectivity). Aspirin acetylates and inhibits both enzymes covalently. Low doses (< 100 mg/day) inhibit preferentially, but not exclusively, platelet COX-1, whereas higher doses inhibit both systemic COX-1 and COX-2. 

Acetic Acid Derivatives and Related Substances (indometacin, diclofenac, sulindac, etodolac, aceclofenac) and structural analogue (lumiracoxib)... 

Diclofenac and Lumiracoxib Novel Mechanisms for Inhibition and COX-2 Selectivity... 

A close structural analog of the non-selective COX inhibitor diclofenac, lumiracoxib displays a 500-fold greater selectivity for COX-2 than COX-1 in vivo and exhibits a unique pharmacologic profile that includes rapid absorbance and a relatively short plasma half-life (41, 42). Lumiracoxib lacks the tricyclic structure of the diarylheterocycle class of COX-2 selective inhibitors (e.g., celecoxib and rofecoxib) and does not contain a sulfonamide or sulfone group. Although structurally related, lumiracoxib and diclofenac exhibit large differences in the selectivity of COX-2 inhibition, and the molecular basis for this... 

Figure 5 Crystal structure of diclofenac bound in the active site of COX-2. The carboxyl group of diclofenac is chelated by Tyr-385 and Ser-530 through hydrogen bonding. The structures of diclofenac and lumiracoxib are shown below. The 5 -methyl group of lumiracoxib is a determinant of COX-2 selectivity, and the dihaloaryl group determines the potency of binding.

As expected from its structural resemblance to diclofenac, lumiracoxib binds to COX-2 in an inverted orientation similar to that of diclofenac with hydrogen-bonding interactions between the carboxylate of the inhibitor and Ser-530/Tyr-385 at the top of the active site (43). A comparison of this crystal structure with a model of lumiracoxib bound to COX-1 leads to the conclusion that the COX-2 selectivity of lumiracoxib arises from the insertion of the methyl group on the phenylacetic acid ring of the inhibitor into a small groove provided by the movement of a primary shell leucine residue (Leu-384) in the COX-2 active site. The movement of Leu-384 is thought to be restricted in the active site of COX-1 because of the presence of bulky secondary shell residues lying behind it (Ile-525 and Phe-503) that prevent the movement of Leu-384 with inhibitor bound. 

The structme-activity studies with diclofenac and lumiracoxib reveal that the COX-2 inhibitory activity of lumiracoxib results from a fine balance between potency and selectivity. The principal determinant of potency is the dUialoarylamine ring, whereas the raefa-methylarylacetic acid ring primarily controls selectivity. An F— C1 substitution in the dihaloarylamine ring of lumiracoxib increases the tightness of binding (potency of... 

Blobaum AL, Marnett LJ. Molecular determinants for the selective inhibition of cyclooxygenase-2 by lumiracoxib. J. Biol. Chem. 2007 282 16379-16390. 

Tannenbaum H, Berenbaum F, Reginster JY, Zacher J, Robinson J, Poor G, Bliddal H, Uebelhart D, Adami S, Navarro F, Lee A, Moore A, Gimona A. Lumiracoxib is effective in the treatment of osteoarthritis of the knee a 13 week, randomised, double blind study versus placebo and celecoxib. Ann. Rheum. Dis. 2004 63 1419-1426. 

Clark K, Kulathila R, Koehn J, Rieffel S, Strauss A, Hu S, Kalfoglou M, Szeto D, Lasala D, Sabio M, Wang X, Marshall P. Crystal stmcture of the lumiracoxib cyclooxygenase-2 complex. In American Chemical Society Book of Abstracts. 2004. pp. 22-26. 

Farkouh ME, Greenberg JD, Jeger RV, Rammanathan K, Verheugt FW. Cardiovascular outcomes in high-risk patients with osteoarthritis treated with ibuprofen. Naproxen, or Lumiracoxib. Ann Rheum Dis 2007 5 [Epub ahead of print]. 

Clinically important, potentially hazardous interactions with acenocoumarol, anagrelide, anticoagulants, bismuth, boswellia, calcium hydroxylapatite, capsicum, cholestyramine, desvenlafaxine, devil s claw, dexamethasone, dexibuprofen, dicumarol, etodolac, evening primrose, flunisolide, ginkgo biloba, ginseng, heparin, ibuprofen, indomethacin, ketoprofen, ketorolac, lumiracoxib, methotrexate, methylprednisolone, nilutamide, NSAIDs, phellodendron, prednisone, resveratrol, reteplase, rivaroxaban, sermorelin, sulfites, tirofiban, triamcinolone, urokinase, valdecoxib, valproic acid, verapamil, warfarin... 

Initially this increased risk of myocardial infarction was attributed to the myocardial protective properties of the nonselective COX inhibitors. COX-2 selective inhibitors may lack this protective capability. Later meta analysis suggested that the degree of myoprotection associated with naproxen could not account for the difference in the incidence of myocardial infarction. Merck, the maker of rofecoxib, withdrew the drug from the market because of this association. The other two coxibs, celecoxib and lumiracoxib, remain on the market as no similar increase in myocardial infarction has been associated with these drugs. It must be stated here that there is controversy regarding this issue and only time will provide the ultimate answer regarding the car-diotoxic potential of these two coxibs. 

Three members of the initial class of COX-2 inhibitors, coxibs, were approved for use in the United States and Europe. Both rofecoxib and valdecoxib have now been withdrawn from the market in view of their adverse event profiles. Two others, parecoxib and etoricoxib, are approved in Europe but still under consideration in the United States. The newest drug in the class, lumiracoxib, is under consideration for approval in Europe and the United States. The relative degree of selectivity for COX-2 inhibition is lumiracoxib = etoricoxib > valdecoxib = rofecoxib celecoxib. However, there is considerable difference in response to the coxibs among individuals, and it is not known how the degree of selectivity may relate to either efficacy or adverse effect profile, although it seems likely to be related to both. No controlled clinical trials comparing outcomes among the coxibs have been performed. 

Diclofenac is the most commonly used tNSAID in Europe. The selective inhibitor of COX-2 lumiracoxib is an analog of diclofenac. 

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