Mini Reviews in Medicinal Chemistry - Volume 4, Issue 6, 2004

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.

The identification and characterization of the inducible form of cyclooxygenases (COX-2) stimulated the investigations to develop efficient, non-steroidal anti-inflammatory drugs (NSAIDs) with reduced side effects (essentially gastro-intestinal toxicity) compared to classical NSAIDs. This review focuses on the chemical and pharmacological properties (pre-clinical data) of marketed COX-2 inhibitors.

The design of selective COX-2 inhibitors is a new approach to obtain potent, anti-inflammatory drugs but with less side effects. Several families of such inhibitors were reported in literature. In this review, the drug design processes used to understand their binding mode and the origin of selectivity of these compounds are described.

Valdecoxib, parecoxib, etoricoxib and lumiracoxib represent the second generation of selective COX-2 inhibitors. In comparison to the first generation, they show an at least equivalent efficacy in the treatment of pain and inflammation. However, the postulated gain of safety is yet difficult to determine and seems to be, if any, small.

The sulfonamides constitute an important class of drugs, with several types of pharmacological agents possessing antibacterial, anti-carbonic anhydrase, diuretic, hypoglycaemic, antithyroid, protease inhibitory and anticancer activity among others. A recently developed class of pharmacological agents incorporating primary sulfamoyl moieties in their molecule is constituted by the COX-2 selective inhibitors, with at least two clinically used drugs, celecoxib and valdecoxib. Another drug of this class, rofecoxib, does not contain sulfonamide moieties, but the isosteric and isoelectronic methylsulfone group. It was recently shown that the sulfonamide COX-2 selective inhibitors (but not the methylsulfone ones) also act as nanomolar inhibitors of several isozymes of the metallo-enzyme carbonic anhydrase (CA), some of which are strongly involved in tumourigenesis. In consequence, the potent anticancer effects of the sulfonamide COX-2 selective inhibitors and the much weaker such effects of rofecoxib, reported ultimately by many researchers, may be explained by the contribution of CA inhibition to such processes in addition to COX-2 inhibition.

Cyclooxygenases and lipoxygenase are key enzymes in the arachidonic acid metabolism. Dual inhibitors are drugs able to block both the COX and the 5-LOX metabolic pathways. Compared to COX or LOX pathways single inhibitors, dual inhibitors present at least two major advantages. First, dual inhibitors, by acting on the two major arachidonic acid metabolic pathways, possess a wide range of anti-inflammatory activities. Secondly, dual inhibitors appear to be almost exempt from gastric toxicity, which is the most troublesome side effect of non-selective COX inhibitors.

Recent advances in topological and structural characterization of the prostacyclin (PGI2) and thromboxane A2 (TXA2) synthases have led to the understanding of the biosynthesis of PGI2 and TXA2 at a structural level. This mini-review focuses on the molecular mechanism of the isomerization of the prostaglandin H2 to PGI2 and TXA2 by their synthases in the endoplasmic reticulum (ER) membrane coordinated with cyclooxygenase-1 or -2. This review summarizes the evidences in which the biosynthesis of PGI2 and TXA2 are influenced / modulated by the membrane anchor residues of the synthases and the ER membrane itself, and provides the structural basis for engineering the synthases for the next generation of gene therapy and drug designs targeting the specific synthases.

Thromboxane A2 (TXA2) is a labile product formed from arachidonic acid by cyclooxygenase. The pathogenesis of numerous cardiovascular, pulmonary, and thromboembolic diseases can be related to this metabolite. Therefore, TXA2 modulators have been developed for 20 years. This review will highlight the evolution in the field of TXA2 modulators.

Increasing interest in the role of ω3 fatty acids has arisen in these latest years since evidence of their implication in the cardioprotective fish based diet of the Inuit has been demonstrated. Furthermore, several in vitro, in vivo and epidemiological studies support the benefit of this fatty acids intake in various pathological states such as in the cardiovascular, cancer, inflammation, psychiatric, paediatric, pulmonary, dermatological and ophthalmologic fields. This review will focus on metabolism and pharmacological implication of ω3 fatty acids intake as well as its interest in the prevention or treatment of the above-mentioned pathologies.

The present review details the rational multi-step process followed for the discovery of a family of non-peptide CCK receptor ligands (“dipeptoids”), starting from the structure of the endogenous peptide, CCK8. Emphasis will be made on the N- and C-terminal modifications, on the singular effects of the stereochemical changes and the incorporation of conformational constraints into the structure of “dipeptoids”, and on the modifications directed to improve the pharmacological profile of these compounds to afford valuable clinical candidates.

The estimation and use of synthetic accessibility in the drug discovery process is discussed. A distinction is drawn between synthetic feasibility and accessibility and the practical uses of an accessibility score are examined. Various techniques used in the estimation of accessibility are described and their utility and potential accuracy compared.

Heparanase is an endo-β-glucuronidase that degrades the glycosaminoglycan heparan sulfate, a major component of the extracellular matrix and basement membranes, and has been implicated in such processes as inflammation, angiogenesis and metastasis. The identification of inhibitors of heparanase is an attractive approach towards developing new therapeutics for metastatic tumours and chronic inflammatory diseases. This review focuses on heparanase inhibitors that have been isolated or synthesised to date. More recent developments in the understanding of heparanase structure and function that may ultimately aid in the future design of inhibitors with improved potency and specificity, are also discussed.