All Title Author
Keywords Abstract

PLOS ONE  2012 

Discovery of Novel Orally Active Anti-Inflammatory N-Phenylpyrazolyl-N-Glycinyl-Hydrazone Derivatives That Inhibit TNF-α Production

DOI: 10.1371/journal.pone.0046925

Full-Text   Cite this paper   Add to My Lib

Abstract:

Herein, we describe the synthesis and pharmacological evaluation of novel N-phenylpyrazolyl-N-glycinyl-hydrazone derivatives that were designed as novel prototypes of p38 mitogen-activated protein kinase (MAPK) inhibitors. All of the novel synthesized compounds described in this study were evaluated for their in vitro capacity to inhibit tumor necrosis factor α (TNF-α production in cultured macrophages) and in vitro MAPK p38α inhibition. The two most active anti-TNF-α derivatives, (E)-2-(3-tert-butyl-1-phenyl-1H-pyrazol-5-ylamino)-N’-((4-(2-morpholinoethoxy)naphthalen-1-y?l)methylene)acetohydrazide(4a) and (E)-2-(3-tert-butyl-1-phenyl-1H-pyrazol-5-ylamino)-N’-(4-chlorobenzylid?ene)acetohydrazide(4f), were evaluated to determine their in vivo anti-hyperalgesic profiles in carrageenan-induced thermal hypernociception model in rats. Both compounds showed anti-inflammatory and antinociceptive properties comparable to SB-203580 used as a standard drug, by oral route at a dose of 100 μmol/kg. This bioprofile is correlated with the ability of NAH derivatives (4a) and (4f) suppressing TNF-α levels in vivo by 57.3 and 55.8%, respectively.

References

[1]  Kapoor M, Martel-Pelletier J, Lajeunesse D, Pelletier JP, Fahmi H (2011) Role of proinflammatory cytokines in the pathophysiology of osteoarthritis. Nat Rev Rheumatol 7: 33–42.
[2]  Pietrzak AT, Zalewska A, Chodorowska G, Krasowska D, Michalak-Stoma A, et al. (2008) Cytokines and anticytokines in psoriasis. Clin Chim Acta 394: 7–21.
[3]  Gardiner TA, Gibson DS, de Gooyer TE, de la Cruz VF, McDonald DM, et al. (2005) Inhibition of tumor necrosis factor-alpha improves physiological angiogenesis and reduces pathological neovascularization in ischemic retinopathy. Am J Pathol 166: 637–644.
[4]  Moller DE (2000) Potential role of TNF-alpha in the pathogenesis of insulin resistance and type 2 diabetes. Trends Endocrinol Metab 11: 212–217.
[5]  Locksley RM, Killeen N, Lenardo MJ (2001) The TNF and TNF receptor superfamilies: Integrating mammalian biology. Cell 104: 487–501.
[6]  Xanthoulea S, Pasparakis M, Kousteni S, Brakebusch C, Wallach D, et al. (2004) Tumor necrosis factor (TNF) receptor shedding controls thresholds of innate immune activation that balance opposing TNF functions in infectious and inflammatory diseases. J Exp Med 200: 367–376.
[7]  Lin J, Ziring D, Desai S, Kim S, Wong M, et al. (2008) TNF alpha blockade in human diseases: An overview of efficacy and safety. Clin Immunol 126: 13–30.
[8]  Tayal V, Kalra BS (2008) Cytokines and anti-cytokines as therapeutics - An update. Eur J Pharmacol 579: 1–12.
[9]  Palladino MA, Bahjat FR, Theodorakis EA, Moldawer LL (2003) Anti-TNF-alpha therapies: The next generation. Nat Rev Drug Discovery 2: 736–746.
[10]  Bongartz T, Sutton AJ, Sweeting MJ, Buchan I, Matteson EL, et al. (2006) Anti-TNF antibody therapy in rheumatoid arthritis and the risk of serious infections and malignancies: Systematic review and meta-analysis of rare harmful effects in randomized controlled trials. JAMA 295: 2482–2482.
[11]  Lee JC, Griswold DE, Votta B, Hanna N (1988) Inhibition of monocyte-Il-1 production by the anti-inflammatory compound SKF-86002. Int J Immunopharmacol 10: 835–843.
[12]  Lee JC, Laydon JT, McDonnell PC, Gallagher TF, Kumar S, et al. (1994) A protein-kinase involved in the regulation of inflammatory cytokine biosynthesis. Nature 372: 739–746.
[13]  Frantz B, Klatt T, Pang M, Parsons J, Rolando A, et al. (1998) The activation state of p38 mitogen-activated protein kinase determines the efficiency of ATP competition for pyridinylimidazole inhibitor binding. Biochemistry 37: 13846–13853.
[14]  Pargellis C, Tong L, Churchill L, Cirillo PF, Gilmore T, et al. (2002) Inhibition of p38 MAP kinase by utilizing a novel allosteric binding site. Nat Struct Biol 9: 268–272.
[15]  Regan J, Breitfelder S, Cirillo P, Gilmore T, Graham AG, et al. (2002) Pyrazole urea-based inhibitors of p38 MAP kinase: From lead compound to clinical candidate. J Med Chem 45: 2994–3008.
[16]  Duarte CD, Barreiro EJ, Fraga CAM (2007) Privileged structures: A useful concept for the rational design of new lead drug candidates. Mini Rev Med Chem 7: 1108–1119.
[17]  Palla G, Predieri G, Domiano P, Vignali C, Turner W (1986) Conformational behavior and E/Z isomerization of N-acyl and N-aroylhydrazones. Tetrahedron 42: 3649–3654.
[18]  Wyrzykiewicz E, Blaszczyk A (2000) New isomeric N-substituted hydrazones of 2-, 3-and 4-pyridinecarboxaldehydes and methyl-3-pyridylketone. J Heterocyclic Chem 37: 975–981.
[19]  Peng YY, Liu HL, Tang M, Cai LS, Pike V (2009) Highly efficient N-monomethylation of primary aryl amines. Chin J Chem 27: 1339–1344.
[20]  Kummerle AE, Raimundo JM, Leal CM, da Silva GS, Balliano TL, et al. (2009) Studies towards the identification of putative bioactive conformation of potent vasodilator arylidene N-acylhydrazone derivatives. Eur J Med Chem 44: 4004–4009.
[21]  Gallily R, Yamin A, Waksmann Y, Ovadia H, Weidenfeld J, et al. (1997) Protection against septic shock and suppression of tumor necrosis factor alpha and nitric oxide production by dexanabinol (HU-211), a nonpsychotropic cannabinoid. J Pharmacol Exp Ther 283: 918–924.
[22]  Mosmann T (1983) Rapid colorimetric assay for cellula growth and survival - Application to proliferation and cyto-toxicity assays. J Immunol Methods 65: 55–63.
[23]  Goettert M, Graeser R, Laufer SA (2010) Optimization of a nonradioactive immunosorbent assay for p38 alpha mitogen-activated protein kinase activity. Anal Biochem 406: 233–234.
[24]  Lavich TR, Cordeiro RSB, Silva PMR, Martins MA (2005) A novel hot-plate test sensitive to hyperalgesic stimuli and non-opioid analgesics. Braz J Med Biol Res 38: 445–451.

Full-Text

comments powered by Disqus

Contact Us

service@oalib.com

QQ:3279437679

微信:OALib Journal