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A New Gateway for Rheumatoid Arthritis: COXIBs with an Improved Cardiovascular Profile

Authors: M. Hoxha, V. Capra, C. Buccellati, A. Sala, C. Cena, R. Fruttero, M. Bertinaria, G. E. Rovati


Today COXIBs are used in the treatment of arthritis and many other painful conditions in selected patients with high gastrointestinal risk and low cardiovascular (CV) risk. Previously, we have identified an unexpected mechanism of action of a traditional non-steroidal anti-inflammatory drug (NSAID) (diclofenac) and a specific inhibitor of cyclooxygenase-2 (COXIB) (lumiracoxib) demonstrating that they possess weak competitive antagonism at the thromboxane receptor (TP). We hypothesize that modifying the structure of a known COXIB so that it becomes also a more potent TP antagonist will preserve the anti-inflammatory and gastrointestinal safety typical of COXIBs and prevent the CV risk associated with long term therapy.

Keywords: Inflammation, cyclooxygenase, lumiracoxib, thromboxane A2

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[1] A. L. Blobaum, L. J. Marnett, ″Structural and functional basis of cyclooxygenase inhibition″, J. Med. Chem. 50, 1425 – 1441, 2007.
[2] Morita, I. "Distinct functions of COX-1 and COX-2,” Prostaglandins Other Lipid Mediat. 68–69, 165–175, 2002.
[3] DeWitt, D.L, "Cox-2-selective inhibitors: the new super aspirins”. Mol. Pharmacol. 55, 625–631, 1999.
[4] T. Grosser, S. Fries, G.A.FitzGerald, "Biological basis for the cardiovascular consequences of COX-2 inhibition: therapeutic challenges and Opportunities,” J. Clin. Invest. 116, 4–15, 2006.
[5] G. A. FitzGerald, ″COXIBs and cardiovascular disease,” N. Engl. J. Med. 351, 1709 – 1711, 2004.
[6] T. Grosser, S. Fries, G. A. FitzGerald, ″Biological basis for the cardiovascular consequences of COX-2 inhibition: therapeutic challenges and opportunities,” J. Clin. Invest. 116, 4–15, 2006.
[7] J. M. Dogn, C. T. Supuran, D. Pratico, "Adverse cardiovascular effects of the COXIBs,” J. Med. Chem. 48, 2251 –2257, 2005.
[8] E. Selg, C. Buccellati, M. Andersson, G.E. Rovati, M. Ezinga, A. Sala, A.K. Larsson, M. Ambrosio, L. Lastbom, V. Capra, B. Dahlen, A. Ryrfeldt, G.C. Folco, S.E. Dahlen, "Antagonism of thromboxane receptors by diclofenac and lumiracoxib,” Br J Pharmacol. 152:1185-1195, 2007.
[9] A. Shenker, P. Goldsmith , C. G. Unson, & A. M. Spiegel, ″The G protein coupled to the thromboxane A2 receptor in human platelets is a member of the novel Gq family. J Biol Chem 266, 9309−9313, 1991.
[10] S. Offermanns, K. Laugwitz, K. Spicher, & G. Schultz, ″ G proteins of the G12 family are activated via thromboxane A2 and thrombin receptors in human platelets,” Proc Natl Acad Sci U S A. 91, 504−508,1994.
[11] DE. Mais, D. De Holl, H. Sightler, PV. Halushka, "Different pharmacologic activities for 13-azapinane thromboxane A2 analogs in platelets and blood vessels,” Eur J Pharmacol. 148(3):309–315,1988.
[12] S.Ratti, P.Quarato, C.Casagrande, R. Fumaagalli, A. Corsini, "Picotamide, an antithromboxane agent, inhibits the migration and proliferation of arterial myocytes,” Eur J Pharmacol. 355(1):77–83, 1998.
[13] SM. Miggin, BT. Kinsella, "Thromboxane A (2) receptor mediated activation of the mitogen activated protein kinase cascades in human uterine smoothmuscle cells,” Biochim Biophys Acta. 1539(1–2):147–162, 2001.
[14] L. Walch, V. de Montpreville, C. Brink, X. Norel, "Prostanoid EP(1)- and TP-receptors involved in the contraction of human pulmonary veins,”. Br J Pharmacol;134(8):1671–1678, 2001.
[15] G.E. Rovati, A. Sala, V. Capra, S.E. Dahlen, G. Folco, "Dual COXIB/TP antagonists: a possible new twist in NSAID pharmacology and cardiovascular risk,” Trends Pharmacol Sci. 31:102-107, 2010.
[16] M. Bertinaria, M.A. Shaikh, C. Buccellati, C. Cena, B. Rolando, L. Lazzarato, R. Fruttero, A. Gasco, M. Hoxha, V. Capra, A. Sala, G.E. Rovati. "Designing Multitarget Anti-inflammatory Agents: Chemical Modulation of the Lumiracoxib Structure toward Dual Thromboxane Antagonists-COX-2 Inhibitors,” ChemMedChem. 7:1647-1660, 2012.