Long-term nonsteroidal anti-inflammatory drugs (NSAIDs) therapy has been associated with several adverse effects such as gastric ulceration and cardiovascular events. Among the molecular modifications strategies, the prodrug approach is a useful tool to discover new safe NSAIDs. The 1-(2,6-dichlorophenyl)indolin-2-one is a diclofenac prodrug which demonstrated relevant anti-inflammatory properties without gastro ulceration effect. In addition, the prodrug decreases PGE 2 levels, COX-2 expression and cellular influx into peritoneal cavity induced by carrageenan treatment. Preliminary pharmacokinetic studies have shown in vivo bioconversion of prodrug to diclofenac. This prodrug is a new nonulcerogenic NSAID useful to treat inflammatory events by long-term therapy.
References
[1]
Cena, C.; Lolli, M.L.; Lazzarato, L.; Guaita, E.; Morini, G.; Coruzzi, G.; McElroy, S.P.; Megson, I.L.; Fruttero, R.; Gasco, A. Antiinflammatory, gastrosparing and antiplatelet properties of new NO-donor esters of aspirin. J. Med. Chem 2003, 46, 747–754.
[2]
Sardi, F.; Fassina, L.; Venturini, L.; Inguscio, M.; Guerriero, F.; Rolfo, E.; Ricevuti, G. Alzheimer’s disease, autoimmunety and inflammation. The good, the bad and the ugly. Autoimmun. Rev 2011, 11, 149–153.
[3]
Charakida, M.; O’Neil, F.; Masi, S.; Papageorgiou, N.; Tousoulis, D. Inflammatory disorders and atherosclerosis: New therapeutic approaches. Curr. Pharm. Des 2011, 17, 4111–4120.
[4]
Cha, Y.I.; DuBois, R.N. NSAIDs and cancer prevention: Targets downstream of COX-2. Annu. Rev. Med 2007, 58, 239–252.
[5]
Becker, R.C. Aspirin and the prevention of venous thromboembolism. N. Engl. J. Med 2012, 366, 2028–2030.
[6]
Rouzer, C.A.; Marnett, L.J. Cyclooxygenases: Structural and functional insights. J. Lipid. Res 2009, 50, S29–S34.
[7]
Go, M.F. Drug injury in the upper gastrointestinal tract: Nonsteroidal anti-inflammatory drugs. Gastrointest. Endosc. Clin. N. Am 2006, 16, 83–97.
[8]
Laine, L. Approaches to nonsteroidal anti-inflammatory drug use in the high-risk patient. Gastroenterology 2001, 120, 594–606.
[9]
Silverstein, F.E.; Graham, D.Y.; Senior, J.R.; Davies, H.W.; Struthers, B.J.; Bittman, R.M.; Geis, G.S. Misoprostol reduces serious gastrointestinal complications in patients with rheumatoid arthritis receiving nonsteroidal anti-inflammatory drugs. A randomized, double-blind, placebo-controlled trial. Ann. Intern. Med 1995, 123, 241–249.
[10]
Mukherjee, D.; Nissen, S.E.; Topol, E.J. Risk of cardiovascular events associated with selective COX-2 inhibitors. J. Am. Med. Assoc 2001, 286, 954–959.
[11]
Wermuth, C.G. Selective optimization of side activities: Another way for drug discovery. J. Med. Chem 2004, 47, 1303–1314.
[12]
Bosquesi, P.L.; Melo, T.R.F.; Vizioli, E.O.; Santos, J.L.; Chung, M.C. Anti-inflammatory drug design using a molecular hybridization approach. Pharmaceuticals 2011, 4, 1450–1474.
[13]
Halen, P.K.; Murumkar, P.R.; Giridhar, R.; Yadav, M.R. Prodrug designing of NSAIDs. Mini Rev. Med. Chem 2009, 9, 124–139.
[14]
Khan, M.S.; Akhter, M. Glyceride derivatives as potential prodrugs: Synthesis, biological activity and kinetic studies of glyceride derivatives of mefenamic acid. Pharmazie 2005, 60, 110–114.
[15]
Halen, P.K.; Chagti, K.K.; Giridhar, R.; Yadav, M.R. Synthesis and pharmacological evaluation of some dual-acting amino-alcohol ester derivatives of flurbiprofen and 2-[1,1′-biphenyl-4-yl]acetic acid: A potential approach to reduce local gastrointestinal toxicity. Chem. Biodivers 2006, 3, 1238–1248.
[16]
Chung, M.C.; Santos, J.L.; Oliveira, E.V.; Blau, L.; Menegon, R.F.; Peccinini, R.G. Synthesis, ex vivo and in vitro hydrolysis study of an indoline derivative designed as an anti-inflammatory with reduced gastric ulceration properties. Molecules 2009, 14, 3187–3197.
[17]
Bandarage, U.K.; Chen, L.; Fang, X.; Garvey, D.S.; Glavin, A.; Janero, D.R.; Letts, L.G.; Mercer, G.J.; Saha, J.K.; Schroeder, J.D.; et al. Nitrosothiol esters of diclofenac: Synthesis and pharmacological characterization as gastrointestinal-sparing prodrugs. J. Med. Chem 2000, 43, 4005–4016.
[18]
Kim, H.; Jeon, H.; Kong, H.; Yang, Y.; Choi, B.; Kim, Y.M.; Neckers, L.; Jung, Y. A molecular mechanism for the anti-inflammatory effect of taurine-conjugated 5-amino-salicylic acid in inflamed colon. Mol. Pharmacol 2006, 69, 1405–1412.
[19]
Pathan, A.R.; Karwa, M.; Pamidiboina, V.; Deshattiwar, J.J.; Deshmukh, N.J.; Gaikwad, P.P.; Mali, S.V.; Desai, D.C.; Dhiman, M.; Thanga Mariappan, T.; et al. Oral bioavailability, efficacy and gastric tolerability of P2026, a novel nitric oxide-releasing diclofenac in rat. Inflammopharmacology 2010, 18, 157–168.
[20]
Agrawal, N.; Chandrasekar, M.J.; Sara, U.V.; Rohini, A. Synthesis, characterization, and in vitro drug release study of methacrylate diclofenac conjugate as macromolecular prodrug. PDA J. Pharm. Sci. Technol 2010, 64, 348–355.
[21]
Tammara, V.K.; Narurkar, M.M.; Crider, A.M.; Khan, M.A. Morpholinoalkyl ester prodrugs of diclofenac: Synthesis, in vitro and in vivo evaluation. J. Pharm. Sci 1994, 83, 644–648.
[22]
Bandgar, B.P.; Sarangdhar, R.J.; Ahamed, F.A.; Viswakarma, S. Synthesis, characterization, and biological evaluation of novel diclofenac prodrugs. J. Med. Chem 2011, 54, 1202–1210.
[23]
Dos Santos, J.L.; Chelucci, R.; Chiquetto, R.; Chung, M.C.; Campos, M.L.; Peccinini, R.G. Synthesis, characterization and pharmacological evaluation of 1-(2-Chloro-6-Fluorophenyl)-5- Methylindolin-2-One: A new anti-inflammatory compound with reduced gastric ulceration properties. Molecules 2010, 15, 8039–8047.
[24]
Winter, C.A.; Risley, E.A.; Nuss, G.W. Carrageenin-induced edema in hind paw of rat as an assay for antiinflammatory drugs. Proc. Soc. Exp. Biol. Med 1962, 111, 544–547.
[25]
Cioli, V.; Putzolu, S.; Rossi, V.; Corza, B.P.; Corradino, C. The role of direct tissue contact in the production of gastrointestinal ulcers by anti-inflammatory drugs in rats. Toxicol. Appl. Pharmacol 1979, 50, 283–289.
[26]
Portanova, J.P.; Zhang, Y.; Anderson, G.D.; Hauser, S.D.; Masferrer, J.L.; Seibert, K.; Gregory, S.A.; Isakson, P.C. Selective neutralization of prostaglandin E2 blocks inflammation, hyperalgesia, and interleukin 6 production in vivo. J. Exp. Med 1996, 184, 883–889.
[27]
Nakamura, M.; Ferreira, S.H. A peripheral sympathetic component in inflammatory hyperalgesia. Eur. J. Pharmacol 1987, 135, 145–153.
[28]
Poole, S.; Lorenzetti, B.B.; Cunha, J.M.; Cunha, F.Q.; Ferreira, S.H. Bradykinin B1 and B2 receptors, tumour necrosis factor alpha and inflammatory hyperalgesia. Br. J. Pharmacol 1999, 126, 649–656.
[29]
Posadas, I.; Bucci, M.; Roviezzo, F.; Rossi, A.; Parente, L.; Sautebin, L.; Cirino, G. Carrageenan-induced mouse paw oedema is biphasic, age-weight dependent and displays differential nitric oxide cyclooxygenase-2 expression. Br. J. Pharmacol 2004, 142, 331–338.
[30]
Elder, D.J.; Paraskeva, C. NSAIDs to prevent colorectal cancer: A question of sensitivity. Gastroenterology 1997, 113, 1999–2003.
[31]
Tegeder, I.; Niederberger, E.; Israr, E.; Gühring, H.; Brune, K.; Euchenhofer, C.; Gr？sch, S.; Geisslinger, G. Inhibition of NF-kappaB and AP-1 activation by R- and S-flurbiprofen. FASEB J 2001, 15, 2–4.
[32]
Gr？sch, S.; Tegeder, I.; Niederberger, E.; Br？utigam, L.; Geisslinger, G. COX-2 independent induction of cell cycle arrest and apoptosis in colon cancer cells by the selective COX-2 inhibitor celecoxib. FASEB J 2001, 15, 2742–2744.
[33]
Maier, T.J.; Janssen, A.; Schmidt, R.; Geisslinger, G.; Gr？sch, S. Targeting the beta-catenin/APC pathway: A novel mechanism to explain the cyclooxygenase-2-independent anticarcinogenic effects of celecoxib in human colon carcinoma cells. FASEB J 2005, 19, 1353–1355.
[34]
Bonaterra, G.A.; Heinrichc, E.U.; Kelberc, O.; Weiserc, D.; Metzd, J.; Kinscherfa, R. Anti-inflammatory effects of the willow bark extract STW 33-I (Proaktiv？) in LPS-activated human monocytes and differentiated macrophages. Phytomedicine 2010, 17, 1106–1113.
Cuzzocrea, S.; Mazzon, E.; Di Paola, R.; Peli, A.; Bonato, A.; Britti, D.; Genovese, T.; Muia, C.; Crisafulli, C.; Caputi, A.P. The role of the peroxisome proliferator-activated receptor-(PPAR-) in the regulation of acute inflammation. J. Leuk. Biol 2006, 79, 999–1010.
[37]
Kaur, J.; Sanyal, S.N. Modulation of inflammatory changes in early stages of colon cancer through activation of PPAR gamma by diclofenac. Eur. J. Cancer Prev 2010, 19, 319–327.
[38]
Kaur, J.; Sanyal, S.N. Diclofenac, a selective COX-2 inhibitor, inhibits DMH-induced colon tumorigenesis through suppression of MCP-1, MIP-1α and VEGF. Mol. Carcinog 2011, 50, 707–718.
[39]
Niederberger, E.; Manderscheid, C.; Geisslinger, G. Different COX-independent effects of the COX-2 inhibitors etoricoxib and lumiracoxib. Biochem. Biophys. Res. Commun 2006, 342, 940–948.
[40]
Malech, H.L.; Gallin, J.I. Current concepts: Immunology. Neutrophils in human diseases. N. Engl. J. Med 1987, 317, 687–694.
[41]
Utsunomiya, I.; Nagai, S.; Oh-ishi, S. Sequential appearance of IL-1 and IL-6 activities in rat carrageenin-induced pleurisy. J. Immunol 1991, 147, 1803–1809.
[42]
Saleh, T.S.; Calixto, J.B.; Medeiros, Y.S. Effects of anti-inflammatory drugs upon nitrate and myeloperoxidase levels in the mouse pleurisy induced by carrageenan. Peptides 1999, 20, 949–956.
[43]
Cuzzocrea, S.; Sautebin, L.; De Sarro, G.; Costantino, G.; Rombola, L.; Mazzon, E.; Ialenti, A.; De Sarro, A.; Ciliberto, G.; Di Rosa, M.; et al. Role of IL-6 in the pleurisy and lung injury caused by carrageenan. J. Immunol 1999, 163, 5094–5104.
[44]
Scheja, A.; Forsgren, A.; Marsal, L.; Wollheim, F. Inhibition of in vivo leucocyte migration by NSAIDs. Clin. Exp. Rheumatol 1985, 3, 53–58.
[45]
Hartmann, P.; Szabó, A.; Eros, G.; Gurabi, D.; Horváth, G.; Németh, I.; Ghyczy, M.; Boros, M. Anti-inflammatory effects of phosphatidylcholine in neutrophil leukocyte-dependent acute arthritis in rats. Eur. J. Pharmacol 2009, 622, 58–64.
[46]
Cardoso, M.L.; Xavier, C.A.C.; Bezerra, M.E.B.; Paiva, A.A.O.; Carvalho, M.; Goretti, F.; Benevides, N.M.B.; Rocha, F.A.C.; Leite, E.L. Assessment of zymosan-induced leukocyte influx in a rat model using sulfated polysaccharides. Planta Med 2010, 76, 113–119.
[47]
Laemmli, U.K. Cleavange of structural proteins during the assembly of the head of bacteriophage T4. Nature 1970, 227, 680–685.
[48]
Pradelles, P.; Grassi, J.; Mac Louf, J. Enzyme immunoassays of eicosanoids using acetylcholine esterase as label: An alternative to radioimmunoassay. Anal. Chem 1985, 57, 1170–1173.
