Inammopharmacology , Vol. 9, No. 1,2, pp. 113–124 (2001) Ó VSP 2001. The pharmacological prole of ML3000: A new pyrrolizine derivative inhibiting the enzymes cyclo-oxygenase and 5-lipoxygenase S. TRIES 1;¤ and S. LAUFER 2 1 R&D Division, Merckle GmbH, Dr.-Georg-Spohn-Str 7, 89143 Blaubeuren, Germany 2 Institute of Pharmacy, University of Tuebingen, D-72076 Tuebingen, Germany Received 14 November 2000; accepted 21 November 2000 Abstract —Since the discovery of aspirin about one century ago, many non-steroidal anti-inam- matory drugs (NSAIDs) have been used for the treatment of inammatory 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 nd 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 LTB 4 and vasoconstrictivepeptidoleukotrienes,the contributoryeffects of which to gastrointestinaldisorders are widely accepted. Therefore, the design of anti-inammatory compounds with 5-LOX inhibitory effects seems reasonable. With the compound ML3000, this theory has gained further evidence. ML3000 is an anti-inammatory compound with potent activity in various animal experiments that represent models for acute and chronic inammation, 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 prole of ML3000, which is currently in Phase III clinical development, is presented in this publication. Key words: [2,2-dimethyl-6-(4-chlorophenyl)-7-phenyl-2,3-dihydro-1H-pyrrolizine-5-yl]-acetic acid; 5-lipoxygenase; anti-inammatory; cyclooxygenase; gastrointestinal; inammation; ML3000; NSAIDs. ¤ To whom correspondence should be addressed. Dr. Susanne Tries, R&D Division, Merckle GmbH, P.O. Box 1161, 89135 Blaubeuren, Germany. E-mail: susatrie@merckle.de