Anti-inflammatory effects and gastrointestinal safety of NNU-hdpa, a novel dual COX/5-LOX inhibitor.
Nonsteroidal anti-inflammatory drugs (NSAIDs) are associated with a risk of serious adverse events. Now, the development of dual inhibitors of cyclooxygenase (COX) and 5-lipoxygenase (5-LOX) has become a hot area in searching for safer NSAIDs. NNU-hdpa, 2-(4-hydroxylphenyl)-3-(3,5-dihydroxylphenyl) propenoic acid, a newly synthesized compound, is expected to have COX/5-LOX dual inhibition with an improved gastrointestinal profile. In this study, NNU-hdpa was subjected to in vitro and in vivo experiment protocols. In vitro COX/5-LOX inhibition assays showed that NNU-hdpa exhibits a dual inhibitory activity against the COX and 5-LOX enzymes. Anti-inflammatory activity in vivo was evaluated using two animal edema model tests. Pretreatment with NNU-hdpa (p.o.) dose-dependently inhibited the xylene-induced ear edema in mice and carrageenan-induced paw edema in rats respectively. In gastric lesion test, NNU-hdpa was gastric-sparing in that it elicited markedly fewer stomach lesions as compared to the stomach lesions caused by aspirin in rats. In further studies, NNU-hdpa was found to significantly inhibit the productions of PGE(2) and LTB(4) in LPS-challenged RAW 264.7, which is parallel to its prevention of the nuclear translocation of the NF-kappaB p50 and p65 subunits. These data indicate that NNU-hdpa comprises a novel class of dual inhibitors of COX and 5-LOX having therapeutic potential with an enhanced gastric safety profile.
Xu
Guang-Lin
GL
Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Science, Nanjing Normal University, Nanjing, PR China. xudunlop@yahoo.com.cn
Liu
Fei
F
Ao
Gui-Zhen
GZ
He
Shu-Ying
SY
Ju
Min
M
Zhao
Yue
Y
Xue
Ting
T
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D002351:Carrageenan / Q000633:toxicity; D002460:Cell Line; D016861:Cyclooxygenase Inhibitors / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D015232:Dinoprostone / Q000378:metabolism; D064420:Drug-Related Side Effects and Adverse Reactions; D004487:Edema / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D007975:Leukotriene B4 / Q000378:metabolism; D016859:Lipoxygenase Inhibitors; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D010666:Phenylpropionates / Q000009:adverse effects* / Q000494:pharmacology* / Q000627:therapeutic use; D011422:Propionates / Q000009:adverse effects* / Q000494:pharmacology* / Q000627:therapeutic use; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D013276:Stomach Ulcer / Q000139:chemically induced*; D014992:Xylenes / Q000633:toxicity
C542254:2-(4-hydroxyphenyl)-3-(3,5-dihydroxyphenyl)propenoic acid; D000893:Anti-Inflammatory Agents; D016861:Cyclooxygenase Inhibitors; D016859:Lipoxygenase Inhibitors; D016328:NF-kappa B; D010666:Phenylpropionates; D011422:Propionates; D014992:Xylenes; D007975:Leukotriene B4; D002351:Carrageenan; D011451:Prostaglandin-Endoperoxide Synthases; C029658:propionic acid; D015232:Dinoprostone