DUAL ACTING ANTI-INFLAMATORY DRUGS

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 (LTB4) 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.