F. Julemont

New Trends in Dual 5-LOX / COX Inhibition

Dual inhibitors are drugs able to block both the COX and the 5-LOX metabolic pathways. The interest of developing such compounds is supported by a large number of pharmacological studies. 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 activity. Secondly, dual inhibitors appear to be almost exempt from gastric toxicity, which is the most troublesome side effect of COX inhibitors. The mechanism of their gastric-sparing properties is not completely understood, although it has been demonstrated that leukotrienes significantly contribute to the gastric epithelial injury. Finally, both COX and LOX derivatives (prostanoids and leukotrienes, respectively) are involved in other diseases than inflammation such as cancer proliferation where the use of dual inhibitors could be an interesting approach.

Pharmacological evaluation of the novel thromboxane modulator BM-567 (II/II). Effects of BM-567 on osteogenic sarcoma-cell-induced platelet aggregation

Evidence exists that a large number of tumor cells such as osteosarcoma cells stimulate platelet aggregation, which can be an early step in the metastatic processes of these tumors. Thromboxane A(2) (TXA(2)) is released during platelet aggregation, and it has been suggested that this release may be pathogenic for tumor metastasis for several reasons:Some tumors release large amounts of TXA(2) compared to normal tissue.TXA(2) potentiates tumor growth in culture and increases metastasis in animals.TXA(2) is a potent stimulant of platelet aggregation and causes vascular injuries that may promote implantation of tumor cell-platelet aggregates. If TXA(2) participates in tumor metastasis, it may be hypothesized that TXA(2) inhibitors should decrease tumor metastasis. So, we have evaluated the effects of the original TXA(2) synthase inhibitor and TXA(2) receptor antagonist BM-567 on platelet aggregation induced by osteosarcoma cells using MG-63 tumor cells. Results obtained showed that this drug inhibited both MG-63 tumor-cell-induced platelet aggregation and platelet TXA(2) release following the tumor cell stimulation with IC(50) values of 3.04x10(-7) and 2.51x10(-8)M, respectively.

Recent Development in the Field of Dual COX / 5-LOX Inhibitors

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.

First and second generations of COX-2 selective inhibitors.

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.

Recent developments in 5lipoxygenase inhibitors

Arachidonic acid (AA) can be metabolised by various enzymes, most notably the cyclooxygenases and the lipoxygenases. The secondary messenger pathway leads to the formation of mediators that are implicated in pathologies such as asthma, inflammation and cancer. Leukotrienes (LTs) are produced through the lipoxygenase pathway. The observation that modulation of leukotriene production by inhibition of 5-lipoxygenase (5-LOX) leads to therapeutic benefit has encouraged research of potent 5-LOX inhibitors. As a consequence, many patents concerning 5-LOX inhibition and the uses of 5LOX inhibitors as therapeutic agents are claimed each year. This article reviews these patents for the period 1999 – 2002.

Advances in the field of COX-2 inhibition

Cyclooxygenase is the key enzyme in the biosynthesis of prostanoids, biologically active substances that are involved in several physiological processes but also in pathological conditions, such as inflammation. It is actually well known that this enzyme exists under two forms: COX-1 and COX-2. Both enzymes are sensitive to inhibition by conventional non-steroidal anti-inflammatory drugs (NSAIDs). Observations that COX-1 was involved in several homeostatic processes, while COX-2 expression was associated with inflammation and other pathologies, such as cancer proliferation, have led to the development of COX-2 selective inhibitors to improve the therapeutic potency and to reduce the classical side effects associated with the use of conventional NSAIDs. A large number of patents concerning COX inhibition are claimed each year and this article reviews patents claimed during the period January 1998 to December 2001.

The use of nimesulide and its analogues in cancer chemoprevention

Non-steroidal anti-inflammatory drugs (NSAIDs), which are known to be cyclooxygenase (COX) inhibitors, have been reported to exert anti-proliferative and pro-apoptotic effects on a variety of cancer cells. Since the COX-2 isoform was found to be overexpressed in a many human cancers, a particular attention was paid on the possible use of selective COX-2 inhibitors in cancer chemoprevention. The present review focuses on the state of the art in cancer research developed with COX-2 preferential/selective inhibitors belonging to the family of N-arylmethanesulfonamides, in particular nimesulide and NS-398.

N-(3-Phenoxy-4-pyridinio)methanesulfonamidate.

The title compound, C(12)H(12)N(2)O(3)S, is a strict pyridine analogue of nimesulide, a selective inhibitor of cyclooxygenase-2. The structure is characterized by a pyridinium ring with a deprotonated sulfonamide group. An intermolecular charge-assisted hydrogen bond between these two groups is observed within the crystal packing, linking the molecules into an infinite chain running along the b-axis direction.