COX-2-specific inhibitors

Workers at Merck recently reported three variants for pyridine formation in conjunction with the synthesis of COX-2-Specific inhibitor 8 (Scheme 1). Acid catalyzed annulation (path a) was achieved in 72% with 2 equivalents of methanesulfonic acid and four equivalents of 2-chloro-3-aminoacrolein. Base-promoted annulation between 7 and 2,3-dichloroacrolein provided 8 in 58% yield. Finally, base-promoted annulation with 2-chloro-iV,jV-dimethyl-armnotrimethinium hexafluorophosphate afforded 8 in 97% yield . Other alkylation-based strategies for pyridine formation include the work of Manna <00BMC1883> and Parra <00S273>. 

Seibert, A single amino acid difference between cyclooxygenase-1 (COX-1) and -2 (COX-2) reverses the selectivity of COX-2 specific inhibitors, J. Biol. Chem. 271 15810... 

Valdecoxib (Bextra Pfizer), a second COX-2 specific inhibitor NSAID was taken off the market a few months after Vioxx. In addition to a higher risk of serious skin toxicity, pahents given Vioxx after Coronary Bypass Surgery had a higher rate of myocardial infarchons. 

Synthesis A number of synthetic strategies to the COX-2 specific inhibitor etoricoxib have been described (Dube et al. (Merck Frosst), 1998 Davies et al., 2000 Sobera et al., 2001a). In schemes 17-20 the two major routes via a dichloropyridine derivative or a ketosulfone, respectively, as the key intermediates are discussed. 

The development of COX-2-specific inhibitors has been helped immensely by knowledge of the detailed three-dimensional structures of COX-1 and COX-2 (Fig. 1). Both proteins are homodimers. Each monomer (A/, 70,000) has an amphipathic domain that penetrates but does not span the ER this anchors the enzyme on the lumenal side of the ER (a very unusual topology—generally the hydrophobic regions of integral membrane proteins span the entire bilayer). Both catalytic sites are on the globular domain protruding into the ER lumen. 

Noveck, R. J., and Hubbard, R. C. Parecoxib sodium, an injectable COX-2-specific inhibitor, does not affect unfractionated heparin-regulated blood coagulation parameters. J. Clin. Pharmacol. 44 474—480, 2004. 

COX-2-specific inhibitors can decrease VEGF-induced endothelial cell proliferation, indicating that COX-2 mediates some of VEGF s angiogenic actions. 

Ibrahim A, Park S, Feldman J, Karim A, Kharasch ED. Effects of parecoxib, a parenteral COX-2-specific inhibitor, on the pharmacokinetics and pharmacodynamics of propofol. Anesthesiology 2002 96(l) 88-95. 

In summary, it is clear that massive amounts of traditional NSAIDs and COX-2 specific inhibitors will continue to be consumed worldwide. Because these... 

Verburg KM, MaziaszTJ, Weiner E et al. Cox-2-specific inhibitors definition of a new therapeutic concept. American Journal of Therapeutics 2001 8 49-64. 

NSAIDs are associated with Gl, renal, liver, or central nervous system toxicity. Appropriate monitoring with complete blood count, serum creatinine, and hepatic transaminase levels is valuable in detecting potential toxicity. Cyclooxygenase-2 (COX-2)-specific inhibitors carry a lower risk of Gl bleeding or platelet inhibition, and may be appropriate in selected patients. 

Despite these complexities, COX-2-specific inhibitors relieve pain in many OA patients with a lower risk of GI adverse events than nonspecific NSAIDs. COX-2 inhibitors, members of the coxib class newly created by the World Health Organization, have become extremely widely used over a short period of time. These agents continue to be studied intensely not only for their efficacy and toxicity profile in rheumatic disease, but also for exciting potential applications such as the prevention of Alzheimer s disease and colorectal cancer. 

In summary, it is clear that massive amounts of traditional NSAIDs and COX-2 specific inhibitors will continue to be consumed worldwide. Because these agents inhibit renal prostaglandin synthesis, they affect salt and water homeostasis and renal hemodynamics. This inhibition will have little clinical effect in the majority of patients who are well-hydrated, have good renal function, and no concomitant disease states. However, both traditional NSAIDs and COX-2 specific inhibitors must be used judiciously in patients with compromised renal blood flow. In general, the COX-2 specific inhibitors are well tolerated by the kidney and it is only in the clinical setting of significant pre-existing renal im-... 

MK 966 Rofecoxib Vioxx. A COX-2 specific inhibitor used in the treatment of osteoarthritis. Analgesic anti-inflammatory. Crystals Sparingly soluble in Me2CO slightly soluble in MeOH, isopropyl acetate very slightly soluble in EtOH practically insoluble in octanol insoluble in H2O. Merck Co.Inc. 

Verburg KM, Maziasz TJ, Weiner E, et al Cox-2-specific inhibitors Definition of a new therapeutic con-... 

Davies et al. have described a new synthetic strategy to obtain the Cox-2 specific inhibitor 251. They heated a mixture of chloromalonaldehyde 249, ammonium acetate, and ketosulfone 250 with propionic acid at 125°C. Pyridine 245 is produced in 62% yield together with furan impurity 252 in approximately 15% yield (Scheme 51) (OOJOC8415). 

Noveck RJ, Kuss ME, Qian J, North J, Hubbard RC. Parecoxib sodium, injectable COX-2 specific inhibitor, does not affect aspirin-mediated platelet function. RegAnes t Penn Med (2001)26(Suppl), 19. 

Karim A Bradford D, Qian J, Hubbard R. The COX-2-specific inhibitor parecoxib sodium does not affect warfarin pharmacokinetic and pharmacodynamic parameters. American College of Emergency Physicians. Scientific Assembly, Chicago, Illinois, 15-18 October 2001. Abstract 130. 

COX-2 Inhibitors Induce Apoptosis with Considerable Differences in Potency. The apoptotic effects of a panel of COX-2-specific inhibitors on human prostate cancer cell lines were evaluated. Table 1 shows that the COX-2 inhibitors, NS398, DuP697, rofecoxib and celecoxib, are similar structurally and with respect to their potencies in COX-2 inhibition (79). In addition, as we reported previously for celecoxib (66), NS398, DuP697, and rofecoxib were capable of inducing apoptosis in both LNCaP and PC-3 cells, as indicated by the characteristic apoptotic features including DNA laddering and caspase-3 (EC 3.4.22.1) activation (Fig. IB and C only data for PC-3 cells is shown). Similarly,... 

Cyclooxygenase (COX)-2-Specific Inhibitors and Respective 50% Inhibitory (IC ) Values in Inhibiting COX-1 and COX-2... 

Joshi GP, Viscusi ER, Gan TJ, et al. Effective treatment of laparoscopic cholecystectomy pain with intravenous followed by oral COX-2 specific inhibitor. Anesth A alg 2004 98 336-342. 

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