Discovery of novel orally active anti-inflammatory N-phenylpyrazolyl-N-glycinyl-hydrazone derivatives that inhibit TNF-α production.
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-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 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.
Laboratório de Avaliação e Síntese de Substâncias Bioativas, Faculty of Pharmacy, Federal University of Rio de Janeiro, Rio de Janeiro, Rio de Janeiro, Brazil.
Renata B
RB
Lacerda
Leandro L
LL
da Silva
Cleverton K F
CK
de Lima
Eduardo
E
Miguez
Ana Luisa P
AL
Miranda
Stefan A
SA
Laufer
Eliezer J
EJ
Barreiro
Carlos A M
CA
Fraga
D000284:Administration, Oral; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D015195:Drug Design; D005260:Female; D006835:Hydrazones / Q000008:administration & dosage / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D051379:Mice; D009281:Naphthalenes / Q000737:chemistry / Q000494:pharmacology; D011720:Pyrazoles / Q000008:administration & dosage / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*; D014508:Urea / Q000737:chemistry; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors; D010671:Phenylurea Compounds
D000894:Anti-Inflammatory Agents, Non-Steroidal; D006835:Hydrazones; D009281:Naphthalenes; D011720:Pyrazoles; D014409:Tumor Necrosis Factor-alpha; D014508:Urea; D048051:p38 Mitogen-Activated Protein Kinases; C580864:2-(3-tert-butyl-1-phenyl-1H-pyrazol-5-ylamino)-N'-((4-(2-morpholinoethoxy)naphthalen-1-yl)methylene)acetohydrazide; C580865:2-(3-tert-butyl-1-phenyl-1H-pyrazol-5-ylamino)-N'-(4-chlorobenzylidene)acetohydrazide; C452139:doramapimod; D010671:Phenylurea Compounds