Preface [Hot Topic: Arachidonic Acid Cascade Modulators: The Cyclooxygenase Pathway (Executive Editors: Jean-Michel Dogné / Xavier de Leval)]

In 1971, more than seventy years after the synthesis of aspirin, John Vane identified cyclooxygenase (COX) as its molecular target. In the early 1990s, a new isoform, cyclooxygenase-2 (COX-2), was discovered. Both isoforms catalyse the transformation of arachidonic acid into endoperoxide H2 as the first step in the biosynthesis of prostanoids, lipidic mediators involved in physiological and pathological processes. In the last several years, researchers and pharmaceutical companies focused their attention on new agents able to interfere with metabolic steps in the degradation of arachidonic acid via the cyclooxygenase pathway. Thus, the identification and characterization of the inducible form of cyclooxygenases (COX-2) stimulated the investigations to develop efficient nonsteroidal anti-inflammatory drugs (NSAIDs) with reduced sideeffects (essentially gastro-intestinal toxicity) compared to classical non-steroidal anti-inflammatory drugs (NSAIDs), which inhibit both COX-1 and COX-2 isozymes. The chemical and pharmacological properties (pre-clinical data) of marketed COX-2 inhibitors of the first and the second generation is reviewed in the first article by Xavier de Leval, co-guest editor. In the second review, Catherine Michaux aims to describe the drug design processes used to understand the binding mode and the origin of selectivity of these COX-2 inhibitors. Dr Dirk Stichtenoth, M.D., focuses his review (paper 3) on the clinical pharmacological applications of the recent selective COX-2 inhibitors valdecoxib, parecoxib, etoricoxib and lumiracoxib. In the fourth review, Dr Claudiu supuran, Ph.D., conducts an examination of the effective antitumor properties of the sulfonamide type COX-2 selective inhibitors. In this paper, the author discusses the hypothesis that the potent anticancer effects of the sulfonamide COX-2 selective inhibitors, reported by many researchers, may be explained by the contribution of carbonic anhydrase inhibition in addition to COX-2 inhibition. In paper 5, Fabien Julémont proposes a complete description of original compounds acting both on the cyclooxygenase-2 and the 5-lipooxygenase, another key enzyme implicated in the AA metabolism. Indeed, in a near future, this class of compound could certainly be of great interest for the treatment of inflammation and others pathologies such as cancer. Thromboxane A2 (TXA2) and prostacyclin (PGI2) are two key metabolites produced by the cyclooxygenase pathway via thromboxane synthase and prostacyclin synthase, respectively. TXA2 has been implicated in various pathophysiological conditions such as thrombosis, stroke, asthma and myocardial infarction due to its potent activating effects on platelet aggregation and smooth muscle contraction. PGI2 is the main arachidonic acid metabolite in vascular walls and has opposing biological properties to TXA2. Indeed, PGI2 represents the most potent endogenous inhibitor of platelet aggregation and is also a strong anti-hypertensive agent through its vasodilatory effects on vascular beds. Recent advances in topological and structural characterization of the prostacyclin and thromboxane A2 synthases have led to the understanding of the biosynthesis of PGI2 and TXA2 at a structural level. Thus, Dr. Ruan, M.D., Ph.D., in his review (paper 6) summarizes the evidences in which the biosynthesis of PGI2 and TXA2 are modulated by the membrane anchor residues of the synthases and the ER membrane itself, and provides the structural basis for engineering the sythases for the next generation of gene therapy and drug designs targeting the specific synthases. Since it is well recognized that TXA2 plays an important role in pathophysiological states, TXA2 receptor antagonists, thromboxane synthase inhibitors, and drugs combining both properties have been developed by several pharmaceutical companies. Some compounds have been launched on the market while others are under clinical evaluation as described in review 7 by Jean-Michel Dogne, Ph.D., co-guest editor. In the eighth review, Isabelle Roland focuses on the metabolism and pharmacological implication of ω3 fatty acids intake as well as its interest in the prevention or treatment of the pathologies where arachidonic acid mediators are implicated. Finally, we want to thank all the authors who kindly agreed to contribute to this hot topic. We also thank the Senior Manager Publications, Miss Afshan Siddiq for her patience when delays in article submissions occurred. Last but not least, we would like to take this opportunity to thank Professor Jacques Delarge (retired Head of the Laboratory of Medicinal Chemistry, University of Liege) for his scientific support during our too short period of collaboration.