New Trends in Dual 5-LOX / COX Inhibition

Abstract

Dual inhibitors are drugs able to block both the COX and the 5-LOX metabolic pathways. The interest of developing such compounds is supported by a large number of pharmacological studies. Compared to COX or LOX pathways single inhibitors, dual inhibitors present at least two major advantages. First, dual inhibitors, by acting on the two major arachidonic acid metabolic pathways, possess a wide range of anti-inflammatory activity. Secondly, dual inhibitors appear to be almost exempt from gastric toxicity, which is the most troublesome side effect of COX inhibitors. The mechanism of their gastric-sparing properties is not completely understood, although it has been demonstrated that leukotrienes significantly contribute to the gastric epithelial injury. Finally, both COX and LOX derivatives (prostanoids and leukotrienes, respectively) are involved in other diseases than inflammation such as cancer proliferation where the use of dual inhibitors could be an interesting approach.

Dual inhibition of 5-lipoxygenase/cyclooxygenase by a reconstituted homeopathic remedy; possible explanation for clinical efficacy and favourable gastrointestinal tolerability

“…Such dual inhibitors are reported to have several advantages over the widely used NSAIDs which preferentially inhibit COX. Among the advantages are a broad range of anti-inflammatory properties as well as a reduction of the NSAID-associated commonly observed gastrointestinal (GI) ulcerogenic activity and bronchospasms [34,35].…”

Quality Control Methods for Standardization of Herbal Products Using Phytomarkers

“…Several derivatives containing pyrazoline, thiophene, di-tert-butylphenol, hydrazone, pyrrolidine and pyrazole subunits have been found to be dual COX/LOX inhibitors. A number of reported dual COX/LOX inhibitors like Licofelone are nitrogen containing heterocycles [21].…”

N-substituted [phenyl-pyrazolo]-oxazin-2-thiones as COX-LOX inhibitors: influence of the replacement of the oxo -group with thioxo- group on the COX inhibition activity of N-substituted pyrazolo-oxazin-2-ones

“…Cyclooxygenase (COX) and lipoxygenase (LOX) produce two groups of arachidonic acid (AA) metabolites, prostaglandins (COX products), leucotrienes and lipoxins (LOX products), that play a key role in inflammation. Traditional NSAIDs which preferentially inhibit COX-1 are associated with gastrointestinal irritation 1 and mild bleeding diathesis. NSAIDs of new generation which selectively inhibit COX-2, lack these side effects.…”

“…Thus, many researchers focused on the development of dual acting COX/LOX inhibitors. 1,2,5 It has been stated that a balanced modulation of several targets can provide superior therapeutic effects and a favorable side effect profile compared to the action of a selective ligand, particularly in cases of complex diseases. 6 Licofelone, a COX-2/5-LOX inhibitor, has been evaluated in a phase III clinical trial.…”

“…7 Among compounds found to be potent dual inhibitors are derivatives of pyrazole, thiophene, indomethacin, dit-butyl-phenol, hydrazone, pyrrole, fenamic acid etc. 1 Most recently Knaus et al 8 tested a number of 1,3-diarylprop-2-yn-1-one as well as rofecoxib derivatives for COX-1, COX-2, and 5, 15 LOX inhibitory activity. Ziakas et al 9 tested a number of tolfenamic and BHT derivatives and Geronikaki et al tested novel thiazolidinone derivatives for COX-1, COX-2 and LOX inhibition.…”