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

作者：Lacerda Renata B; da Silva Leandro L; de Lima Cleverton K F; Miguez Eduardo; Miranda Ana Luisa P; Laufer Stefan A; Barreiro Eliezer J; Fraga Carlos A M^*

来源：PLos One, 2012, 7(10): e46925.

DOI：10.1371/journal.pone.0046925

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 alpha (TNF-alpha production in cultured macrophages) and in vitro MAPK p38 alpha inhibition. The two most active anti-TNF-alpha derivatives, (E)-2-(3-tert-butyl-1-phenyl-1H-pyrazol-5-ylamino)-N%26apos;-((4-(2-morpholinoethoxy)naphthalen-1-yl)methylene)acetohydrazide (4a) and (E)-2-(3-tert-butyl-1-phenyl-1H-pyrazol-5-ylamino)-N%26apos;-(4-chlorobenzylidene)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 mu mol/kg. This bioprofile is correlated with the ability of NAH derivatives (4a) and (4f) suppressing TNF-alpha levels in vivo by 57.3 and 55.8%, respectively.

• 出版日期2012-10-8