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

• Published in: PloS one 2012-10, Vol.7 (10), p.e46925
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: Anti-inflammatory agents; Carrageenan; Derivatives (Financial instruments); Tumor necrosis factor
• ISSN: 1932-6203; 1932-6203
• 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'-((4-(2-morpholinoethoxy)naphthalen-1-yl)methylene)acetohydrazide (4a) and (E)-2-(3-tert-butyl-1-phenyl-1H-pyrazol-5-ylamino)-N'-(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 [micro]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.