Pharmaceutical and Medicinal Chemistry

Eicosanoides in inflammation

Eicosanoids in Inflammation and Cancer

3rd Generation NSAIDs (non steroidal anti-inflammatory drugs)

Rheumatic diseases such as osteoarthritis (OA) and rheumatoid arthritis (RA) are major causes of disability in Western countries, inflammation and pain are the main causes of the progressive and destructive process in OA and RA.

In the current disease management approach, non-steroidal anti-inflammatory drugs (NSAIDs) play an important role. An improvement in the patients condition is achieved by the peripheral analgesic effect and the anti-inflammatory action. However, the use of NSAIDs may result in gastro-intestinal side effects, which range from mild symptoms such as dyspepsia and abdominal discomfort to more serious adverse events such as peptic ulcers, life-threatening gastric/duodenal bleeding and perforation.

The commonly accepted mechanism of action of NSAIDs is the inhibition of cyclooxygenase (COX). COX is a key enzyme in the metabolic pathway leading from arachidonic acid to pro-inflammatory prostaglandins and thromboxanes (Figure 1). The inhibition of COX results in a reduced synthesis of prostaglandins and thromboxanes and is the basis for the anti-inflammatory efficacy and probably also for the analgesic activity of NSAIDs.
However, this same COX inhibition also leads to gastro-intestinal adverse effects due to reduction of gastro-protective prostaglandins. This effect is modified by specific inhibition of the COX-2 isoenzyme which, in contrast to the COX-1 isoenzyme, is not expressed in the gastric mucosa under natural conditions
On the other hand, the inhibition of COX leads to a shunt to the 5-lipoxygenase (5-Lox) pathway (Figure 2). 5-LOX is the second key enzyme in the arachidonic acid metabolism and leads to the formation of leukotrienes. Leukotrienes induce gastric lesions and ulceration due to leukocyte adhesion and vasoconstriction in the gastric mucosa.
This shift from the COX pathway to the 5-Lox pathway is an important reason for the poor gastro-intestinal tolerability of NSAIDs.

The dual inhibition of COX and 5-Lox would be expected to achieve better gastro-intestinal tolerability.
Dual inhibitors of COX and 5-LOX may be considered a distinct class of drugs. Dual acting anti-inflammatory drugs (3rd generation NSAIDs) would be expected to combine good anti-inflammatory and analgesic activities with excellent gastro-intestinal tolerability. Several drugs have proven this new principle in preclinical pharmacological and toxicological investigations

ML3000 (INN: Licofelone) is a novel, potent, balanced, competitive inhibitor of both COX and 5-LOX.

ML3000 has succeeded in clinically validating this mechanism of action.