%0 Journal Article
%T Discovery of Novel Orally Active Anti-Inflammatory N-Phenylpyrazolyl-N-Glycinyl-Hydrazone Derivatives That Inhibit TNF-¦Á Production
%A Renata B. Lacerda
%A Leandro L. da Silva
%A Cleverton K. F. de Lima
%A Eduardo Miguez
%A Ana Luisa P. Miranda
%A Stefan A. Laufer
%A Eliezer J. Barreiro
%A Carlos A. M. Fraga
%J PLOS ONE
%D 2012
%I Public Library of Science (PLoS)
%R 10.1371/journal.pone.0046925
%X 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 ¦Á (TNF-¦Á production in cultured macrophages) and in vitro MAPK p38¦Á inhibition. The two most active anti-TNF-¦Á derivatives, (E)-2-(3-tert-butyl-1-phenyl-1H-pyrazol-5-ylamino)-NˇŻ-((4-(2-morpholinoethoxy)naphthalen-1-yŁżl)methylene)acetohydrazide(4a) and (E)-2-(3-tert-butyl-1-phenyl-1H-pyrazol-5-ylamino)-NˇŻ-(4-chlorobenzylidŁżene)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 ¦Ěmol/kg. This bioprofile is correlated with the ability of NAH derivatives (4a) and (4f) suppressing TNF-¦Á levels in vivo by 57.3 and 55.8%, respectively.
%U http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0046925