Current Medicinal Chemistry - Volume 7, Issue 11, 2000

The identification and characterisation of the isoenzyme cyclooxygenase 2 (COX-2) stimulated investigations to develop efficient non-steroidal anti-inflammatory drugs with reduced side effects compared to standard NSAIDs.This review will focus on the structural features needed to achieve COX-2 selectivity. Five structural classes can be identified together with a class bearing little or no resemblance to one another in their molecular structure. The most interesting point is the very distinct structure/activity relationship. On the one hand only minor modifications to a particular compound induce a drastic change in its COX selectivity and on the other hand the structural prerequisites in terms of molecular shape, lipophilicity, electron density, flexibility, polarity and H-bonding dynamics allow a wide range of diversity

Following the discovery of inducible COX-2 in arthritic joint fluid and immunocompetent cells a revolution in the field of antiinflammatory treatment was expected. The detection of a constitutive COX-2 in the kidney, in stomach and central nervous system destroyed this hypotheses.Further experiments in animal models were done to elucidate the role of the constitutive COX-2 in different physiological and pathophysiological states. In central nervous system was shown that the constitutive COX-2 is the predominant isoform of cyclooxygenases in brain and spinal cord and is highly regulated by different mediators. After experimental induction of peripheral inflammation a significant induction of COX-2 gene, protein expression and synthesis of prostaglandins in the spinal cord was detected. It was concluded that COX-2 is strongly involved in pain mediation processing in the spinal cord. The detection of COX-2 in the brain endothelial cells and its role in fever led to new insights of development and time course of temperature elevation. Probably, the use of selective COX-2 inhibitors decreases fever more effective than ‘classical’ antipyretics. Furthermore, newer results show a role of COX-2 in differentiation and maturation processes in brain. These findings implicate new ways for the treatment of Alzheimer's disease and other degenerative brain disorders.Clinical and experimental results with selective COX-2 inhibitors show a better safety profile than non-selective COX inhibitors. The clinical use after drug registration will be decide on the further role of this new class of drugs in analgesic/antiinflammatory therapy and on new fields of clinical use.

Inhibition of prostaglandin biosynthesis via inhibition of the fatty acid cyclooxygenase (COX) is the mechanism of action of non-steroidal anti-inflammatory drugs (NSAIDs). This results in an inhibition of the inflammatory and pain-producing activities of prostaglandins at a site of tissue injury but also in inhibition of prostaglandin production in the gastrointestinal tract (GI) and platelets, i.e. sites where endogenous prostaglandins are possibly involved in control of physiological functions. The discovery of two COX isoenzymes, COX-1 and COX-2, and the detection of their separate function and regulation, has initiated the search for new and putatively more selective inhibitors of prostaglandin biosynthesis. Specifically, selective inhibitors of COX-2 were developed in order to improve the anti-inflammatory and analgetic specificity and potency of the compounds and to reduce side-effects in the GI tract. Available experimental and clinical data of selective COX-2 inhibitors, including flosulide, celecoxib or rofecoxib, suggest improved gastric tolerance as compared to conventional, non-selective NSAIDs. However, experimental evidence suggests that both, the analgetic and anti-inflammatory action of COX-inhibitors, might also require inhibition of COX-1. COX-2-selective compounds at anti-inflammatory doses might have other side-effects, and for example reduce vascular prostacyclin production. Evidence is accumulating that COX-2 might not only be considered as a putatively detrimental enzyme but rather a highly regulated enzyme that also contributes to tissue protection and is even constitutively expressed in healthy human stomach mucosa. This paper reviews some of these newer aspects of COX-2-selective inhibitors in clinical use and discusses their possible benefits and risks.

Non-steroidal anti-inflammatory drugs (NSAIDs) have as their common mechanism the inhibition of cyclooxygenase (COX) enzymes, of which two isoforms (COX-1 and COX-2) exist. The effect of NSAIDs on chemoprevention and tumor regression has been shown in animal models, epidemiologic studies, and in treatment of patients. The exact biochemical and cellular mechanisms underlying each of these phenomena is only partially understood. Processes that have been recently implicated as being important include the inhibition of tumor cell growth, prevention of angiogenesis, and induction of apoptosis in neoplastic cells.

Increasing amounts of experimental and clinical data support the role of selective cyclooxygenase (COX)-2 inhibition in anti-inflammatory processes and the involvement of COX-1 inhibition in the side effects associated with non steroidal anti-inflammatory drug use. This review will focus on the differences in the structure of the COX-1 and COX-2 molecules, particularly the active site and how they are bound by various NSAIDs to achieve COX-2 selectivity. This COX-2 selectivity will then be characterized in pharmacological assays in vitro and in animal models in vivo. Finally, clinical information available for this new class of selective inhibitors will be discussed.

Angiogenesis is the process by which new blood vessels are formed. This process supports normal physiology as well as contributes to progression of disease. Progressive rheumatoid arthritis and growth of tumors are two pathologies to which angiogenesis contributes. In arthritis, we know that prostaglandins (PGs) and the enzyme cyclooxygenase-2, which catalyses prostaglandin production, are inflammatory mediators. These mediators are involved in rheumatoid arthritis and cancer-induced angiogenic processes. We discuss, herein, recent findings on the expression of cyclooxygenases in both rheumatoid arthritis and human cancer, and the links between COX-2, PGs, and angiogenesis. We also propose a model for the possible mechanistic interaction of the various cell types involved in angiogenesis.