The pharmacological profile of ML3000: A new pyrrolizine derivative inhibiting the enzymes cyclo-oxygenase and 5-lipoxygenase

Since the discovery of aspirin about one century ago, many non-steroidal anti-inflammatory drugs (NSAIDs) have been used for the treatment of inflammatory states and pain. While the NSAIDs are generally safe and effective, common side effects frequently limit therapy. Typical mechanism-based side effects are gastrointestinal (GI)-related, ranging from GI upset and intolerance to ulceration and bleeding after long-term therapy. In order to overcome these side effects several strategies have been followed, among them the development of selective COX-2 inhibitors. Our strategy to find compounds that are active on the one hand and tolerated by the GI tract on the other hand, is based on the shunt to leukotrienes. This theory is founded upon the fact that NSAIDs, while inhibiting the cyclooxygenase branch of the arachidonic acid cascade, are able to increase the 5-lipoxygenase (5-LOX) branch of arachidonic acid metabolism. This shunt to the 5-LOX side leads to the increase in chemotactic LTB4 and vasoconstrictive peptidoleukotrienes, the contributory effects of which to gastrointestinal disorders are widely accepted. Therefore, the design of anti-inflammatory compounds with 5-LOX inhibitory effects seems reasonable. With the compound ML3000, this theory has gained further evidence. ML3000 is an anti-inflammatory compound with potent activity in various animal experiments that represent models for acute and chronic inflammation, pain, fever and asthma. It is a balanced inhibitor of the enzymes 5-LOX and COX-1/2 in the submicromolar range. The compound demonstrates excellent gastrointestinal tolerance in various animal species. The preclinical profile of ML3000, which is currently in Phase III clinical development, is presented in this publication.