Dual Acting Anti-Inflammatory Drugs

Abstract

Drugs able to inhibit both cyclooxygenases (COX-1 and COX-2) and 5-lipoxygenase (5-LOX) (dual acting anti-inflammatory drugs) have been designed in order to obtain compounds that retain the activity of classical nonsteroidal anti-inflammatory drugs (NSAIDs) while avoiding their main drawbacks. The classical NSAIDs display their anti-inflammatory action mainly through inhibition of COX and one of their main drawbacks is the curtailed production of gastroprotective prostaglandins (PGs) being associated with the concurrent increased production of the gastro-damaging and bronchoconstrictive leukotrienes (LTs). Leukotrienes and cysteinyl-leukotrienes are moreover pro-inflammatory and increase microvascular permeability. One of the leukotrienes (LTB(4)) is the most potent chemotactic agent and it induces chemotaxis of eosinophils, neutrophils and monocytes in the inflamed tissue, increases superoxide generation and proinflammatory cytokines production. It is further advantageous for a drug to have both COX and 5-LOX inhibiting activities because prostaglandins enhance leukotriene-mediated inflammation. Various structural families of dual inhibitors have been designed and several compounds are currently undergoing clinical development. In the post-COX-2 selective inhibitors era, these dual acting inhibitors may turn out to be promising new drugs to treat inflammatory diseases and possibly other diseases. Indeed, both COX-2 and 5-LOX are also involved in the development and progression of several types of cancer; in these conditions, selective inhibition of COX-2 alone may lead to a shunt of arachidonic acid metabolism towards the leukotriene pathway, and therefore the blockade of both COX-2 and 5-LOX may produce a better anticancer response. In addition, the dual inhibition of both COX and 5-LOX is neuroprotective by suppressing toxic actions of reactive microglia and macrophages, that are increased in aging brain and in age-related degenerative conditions, particularly Alzheimer's and Parkinson's diseases. Finally, the blockade of 5-LOX does not impair the synthesis of lipoxins (LXs), which are mainly produced by further lipoxygenation of 15-HPETE, and which have potent anti-inflammatory properties and can be considered as stop-signal mediators. Leukocyte 15-LOX and platelet 12-LOX by intercellular mechanism via leukocyte/platelet cell-cell interaction convert 15-HPETE into lipoxins.

Inhibition of lipoxygenases and cyclooxygenases by linoleyl hydroxamic acid: comparative in vitro studies

“…However, one should note that COX2 is the main target of aspirin and other nonsteroidal antiinflammatory drugs (NSAIDs), and it is its inhibition that is believed to be responsible for the most harmful side effects of NSAIDs. Currently, dual COX/LO inhibitors are a popular trend (79)(80)(81)(82). This approach promises to simultaneously reduce biosynthesis of proinflammatory prostaglandins and leukotrienes, thus minimizing the risk of developing post-treatment complications such as ulceration of the gastrointestinal tract or cardiovascular disorders.…”

Regulation of pro-inflammatory responses by lipoxygenases via intracellular reactive oxygen species in vitro and in vivo

“…During in vivo inflammatory responses, the leukotrienes (LTs) B4, C4, D4, and E4 generated by the 5-LOX pathway of arachidonic acid metabolism have been experimentally determined to perform a function in each of these inflammatory mechanisms (Samuelsson et al, 1983;O'Byrne et al, 1997). Clinical and experimental studies have shown that selective LTD 4 receptor antagonists, including pranlukast, zafirlukast, MK-571, and MK-679 have potential effects with regard not only to the amelioration of asthma symptoms, but also in terms of the use of β 2-agonists and bronchoconstriction induced by exposure to allergens, exercise, aspirin, and cold air (Samuelsson et al, 1983;O'Byrne et al, 1997;Gaddi et al, 2004;Leone et al, 2007).…”

Dual inhibition: a novel promising pharmacological approach for different disease conditions

“…Furthermore, the dual inhibition of both COX and 5-LOX is neuroprotective, and thus these drugs can be beneficial, particularly in ADs and PDe. [76] Other emerging dual anti-inflammatory drugs are flavocoxid, ML3000 (2,2-dimethyl-6-(4-chlorophenyl)-7-phenyl-2,3-dihydro-H-pyrrolizine-5-yl) acetic acid and some virtually designed thiazolidinones (Figure 1o). [28,29] Cardiovascular diseases: congestive heart failure Dual b and a1 adrenergic receptor antagonists Some third-generation b-receptor antagonists also block b1 adrenergic receptors.…”