Current Topics in Medicinal Chemistry - Volume 7, Issue 3, 2007

Significant advances for treating the signs and symptoms of inflammatory disease have been made in the last decade. Most of the existing anti-inflammatory drugs are effective, but not without adverse effects. Various strategies have been employed to overcome the major problem of the gastrointestinal (GI) toxicity that may accompany the long-term use of the traditional nonsteroidal anti-inflammatory drugs (NSAIDs). Among the most high-profile of these strategies in recent years has been the development of cyclooxygenase-2 (COX-2) selective inhibitors. The discovery of COX-2 identified an enzyme that is specifically upregulated during inflammation to produce proinflammatory prostaglandins (PGs). Selective COX-2 inhibition was thus embraced by many pharmaceutical companies as a major therapeutic and commercial goal predicated upon the “COX-2 hypothesis”: selective COX-2 inhibition should obviate the GI toxicity of nonselective NSAIDs by blocking selectively pro-inflammatory PG synthesis at inflammatory sites without interfering with gastroprotective PG production by cyclooxygenase-1 (COX-1) in the GI tract. Over the last fifteen years, remarkable accomplishments have been made on the synthesis of structurally diverse COXIBs, the identification of COXIBs with attractive preclinical profiles, and COXIB clinical development and marketing. As anti-inflammatory medicines, COXIBs proved just as effective as classical NSAIDs, but with reduced GI side-effects and notably better GI tolerability. By 2001, COXIBs had established a virtually unprecedented record in the pharmaceutical industry for global sales growth, sustained by an aggressive marketing program focused on COXIB GI safety. Since highly selective COX-2 inhibitors attenuate production of prostacyclin (PGI2), an important anti-thrombotic eicosanoid, theoretical concerns were voiced as early as 1999-2001 about their potential to precipitate cardiovascular events. In September, 2004, Merck voluntarily withdrew rofecoxib from the market in the face of clinical data from the APPROVe trial showing that subjects who had taken 25 mg rofecoxib/day for more than 18 months had a four-fold greater incidence of serious thromboembolic events and a doubling of the myocardial infarction rate vs. the placebo group. Subsequent reports provided compelling clinical evidence that structurally diverse COXIBs carry an enhanced cardiovascular risk that is likely a dosedependent class effect, especially for patients already at moderate-to-high risk of cardiovascular disease. Although in February, 2005, an FDA panel reviewed the cardiovascular safety of COXIBs and voted to allow their continued use, in April of that year the FDA requested withdrawal of valdecoxib (and its intravenously administered prodrug, parecoxib) from the market due to a cluster of cardiovascular events in treated patients undergoing coronary bypass graft surgery. The COXIB trajectory as a parabola spanning almost a decade stands as one of the biggest disappointments in the pharmaceutical industry and invites new thinking and approaches. In this issue, recent developments in anti-inflammatory drug development as well as possible future strategies have been reviewed. The status of currently available COX-2 inhibitor “Celecoxib” and its safety are presented in detail in the first contribution. Gajraj gives an outstanding in-depth overview of COX-2 inhibitors celecoxib and parecoxib as valuable options for postoperative pain management. Kulkarni and Singh describe “Licofelone a novel dual acting COX/5-LOX inhibitor” in the second contribution and give an up-to-date overview that covers our contemporary understanding of pathogenic mechanisms in inflammatory conditions, NSAID-induced adverse GI effects, and the rationale for the development of “Licofelone” (a dual 5-LOX/COX inhibitor) with data on its in vivo efficacy, pharmacodynamic activity, clinical studies, and comparison with COX-2 selective and nonselective inhibitors. The third contribution describes the development of dual acting anti-inflammatory drugs and the rationale for the development of dual acting drugs. Leone, Ottani and Bertolini gave an interesting overview of this topic, which also includes 5-LO expression and implication of 5-LO derived leukotrienes (LTs) in atherosclerosis and cardiovascular inflammation, an area that is currently receiving considerable attention. As alternatives to highly-selective COX-2 inhibitors, COX inhibiting nitric oxide (NO) donating drugs (CINODs) (previously termed “NO-NSAIDs”) have attracted interest. Nitroalkoxy esters of traditional NSAIDs are pro-drugs that are hydrolyzed to the parent NSAID and the nitroalkoxy ester. The nitroalkoxy ester can produce NO, presumably by physiological routes of reductive organic nitrate metabolism.......

COX-2 inhibitors are equally as efficacious as the non-selective NSAIDs for the treatment of postoperative pain, but have the advantages of a better gastrointestinal side-effect profile as well as a lack of antiplatelet effects. There have been recent concerns regarding the cardiovascular side effects of COX-2 inhibitors. Nonetheless, they remain a valuable option for postoperative pain management. The pharmacology of these agents and available studies are reviewed.

Dual inhibitors that block both cyclooxygenase (COX) and lipoxygenase (LOX) metabolic pathways of arachidonic acid are expected to possess clinical advantages over the selective inhibitors of COX enzyme. One of the most promising compounds belonging to this category is licofelone ([2,2 -dimethyl -6-(4-chloropheny-7-phenyl-2,3-dihydro- 1H-pyrrazoline-5-yl] acetic acid). Originally discovered by Merckle GmbH and developed by EuroAllaince, licofelone (IC50 COX=0.21 μM, IC50 5-LOX=0.18μM) possesses significant analgesic, anti-inflammatory, and antiasthmatic effects at doses that cause no gastrointestinal (GI) side effects. The pharmacodynamic profile of licofelone has been assessed and compared with widely used NSAIDs in different animal models. The ED50 value of licofelone is reported to be 11.22- 27.07 mg/kg, po and 39.5-55-8 mg/kg, po against carrageenan-induced paw oedema and Randal Selitto hyperalgesic assay in rats, respectively. Licofelone showed analgesic effect (ED50 = 31.33 mg/kg) against acetic acid-induced writhing in mice. Licofelone has long duration of action and more effective than indomethacin and zileuton with ED50 values of 2.92 mg/kg, po and 36.77 mg/kg, po, in the mechanical hyperalgesia and cold allodynia testing, respectively, against rat model of incisional pain. Licofelone significantly ameliorated indomethacin-induced gastric ulceration, neutrophil adhesion in mesentery, and lipid peroxides in rat gastric mucosa. Also, licofelone reversed the altered vascular permeability, morphological changes, and prevented NSAIDs-related increase in leukotriene levels in gastric mucosa. The preclinical studies have shown that licofelone not only has convincing pharmacodynamic effect but also it is well tolerated. It is currently under clinical evaluation in osteoarthritis (OA), the most common form of arthritis. The present review describes pharmacological and clinical development of licofelone as a dual inhibitor.

Drugs able to inhibit both cyclooxygenases (COX-1 and COX-2) and 5-lipoxygenase (5-LOX) (dual acting anti-inflammatory drugs) have been designed in order to obtain compounds that retain the activity of classical nonsteroidal anti-inflammatory drugs (NSAIDs) while avoiding their main drawbacks. The classical NSAIDs display their antiinflammatory action mainly through inhibition of COX and one of their main drawbacks is the curtailed production of gastroprotective prostaglandins (PGs) being associated with the concurrent increased production of the gastro-damaging and bronchoconstrictive leukotrienes (LTs). Leukotrienes and cysteinyl-leukotrienes are moreover pro-inflammatory and increase microvascular permeability. One of the leukotrienes (LTB4) is the most potent chemotactic agent and it induces chemotaxis of eosinophils, neutrophils and monocytes in the inflamed tissue, increases superoxide generation and proinflammatory cytokines production. It is further advantageous for a drug to have both COX and 5-LOX inhibiting activities because prostaglandins enhance leukotriene-mediated inflammation. Various structural families of dual inhibitors have been designed and several compounds are currently undergoing clinical development. In the post-COX-2 selective inhibitors era, these dual acting inhibitors may turn out to be promising new drugs to treat inflammatory diseases and possibly other diseases. Indeed, both COX-2 and 5-LOX are also involved in the development and progression of several types of cancer; in these conditions, selective inhibition of COX-2 alone may lead to a shunt of arachidonic acid metabolism towards the leukotriene pathway, and therefore the blockade of both COX-2 and 5-LOX may produce a better anticancer response. In addition, the dual inhibition of both COX and 5-LOX is neuroprotective by suppressing toxic actions of reactive microglia and macrophages, that are increased in aging brain and in age-related degenerative conditions, particularly Alzheimer's and Parkinson's diseases. Finally, the blockade of 5-LOX does not impair the synthesis of lipoxins (LXs), which are mainly produced by further lipoxygenation of 15-HPETE, and which have potent anti-inflammatory properties and can be considered as stop-signal mediators. Leukocyte 15-LOX and platelet 12-LOX by intercellular mechanism via leukocyte/platelet cell-cell interaction convert 15-HPETE into lipoxins.

Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used drugs but their use is hampered by gastrointestinal side effects. Cyclo-oxygenase Inhibitor Nitric Oxide Donors (CINODs) are a new class of antiinflammatory and analgesic drugs generated by adding a nitric oxide generating moiety to the parent NSAID via an ester linkage. The combination of balanced inhibition of the two main COX isoforms with release of NO confers to CINODs a reduced gastrointestinal toxicity and a potent anti-inflammatory activity. It is suggested that the NO, which is released by the metabolism of nitrate as the compounds are broken down, may counteract the consequences of the NSAID-induced decrease in gastric mucosal prostaglandins. Recent clinical trials with CINODs (previously termed NO-NSAIDs) have provided data consistent with pre-clinical observations

Emerging reports now indicate alterations of arachidonic acid metabolism with carcinogenesis and many COX and LOX inhibitors (used for the treatment of inflammatory diseases) are being investigated as potential anticancer drugs. Results from clinical trials seem to be encouraging but a better knowledge of the dynamic balance that shifts toward lipoxygenases (and different isoforms of LOXs) and cyclooxygenase-2 are essential to progress in the design of new drugs more specially directed on chemoprevention or chemotherapy of human cancers. So, on the basis of these results, it seemed useful to study the advantages of combination of COX inhibitor with LOX inhibitor and a next step will be the conception of dual inhibitors able to induce the anticarcinogenic and/or to inhibit the procarcinogenic enzymes responsible for polyunsaturated fatty acid metabolism. After a rapid summary of some recent reviews published on the involvement of different COX and LOX isoforms present in human cells, we will discuss on cross-talk reported between the downstream pathways which contribute to the development and progression of human cancers. This will lead us to evoke and to justify alternative strategies to develop agents that modulate multiple targets simultaneously with the aim of enhancing efficacy or improving safety relative to drugs that address only a single enzyme.

The eicosanoid family comprises a number of biologically active lipid mediators involved in the regulation of inflammation and cancer cell growth. Eicosanoid biosynthesis is usually initiated by the release of arachidonic acid (AA) from membrane phospholipids in response to the interaction of a phospholipase-A2 (PLA2) stimulus with a receptor on the cell membrane. The free released AA is subsequently metabolized by three major enzymatic pathways: the cyclooxygenase (COX), lipoxygenase (LO) and cytochrome P450-dependent pathways. The COX pathway transforms AA into prostaglandins (PGs) and is of particular clinical relevance because it is the main target for non-steroidal antiinflammatory drugs (NSAIDs). Of interest, COX-2, one of the two COX isoforms, is primarily involved in inflammation and cancer and for this reason selective COX-2 inhibitors have been developed. The efficacy of these compounds is similar to that of traditional NSAIDs but with a lower risk of gastrointestinal toxicity and bleeding. On the other hand, emerging information has recognized the role of other AA metabolites derived from the 5-LO pathway, the leukotrienes (LTs), in mediating and maintaining inflammation. Consequently, drugs able to inhibit 5-LO are now included among the effective pharmacological therapies, especially in asthma and allergic inflammation. Moreover, COX-2 and 5-LO pathways appear to act in parallel in the regulation of cell proliferation and neo-angiogenesis and both COX-2 and 5-LO inhibitors are being investigated as potential anticancer drugs. This review article will update the progress achieved in the knowledge of COX-2 and 5-LO and discuss the emerging approaches for the pharmacological modulation of these pathways.

In mammalian cells, eicosanoid biosynthesis is usually initiated by the activation of phospholipase A2 and the release of arachidonic acid (AA) from membrane phospholipids. The AA is subsequently transformed by cyclooxygenase (COX) and lipoxygenase (LO) pathways to prostaglandins, thromboxane and leukotrienes collectively termed eicosanoids. Eicosanoid production is considerably increased during inflammation. Both COX and LO pathways are of particular clinical relevance. The COX pathway is the major target for non-steroidal anti-inflammatory drugs (NSAIDs), the most popular medications used to treat pain, fever and inflammation. Although their anti-inflammatory effects are well known, their long-term use is associated with gastrointestinal (GI) complications such as ulceration. In 1991, it was discovered that COX exists in two distinct isozymes, COX-1 and COX-2, of which COX-2 is primarily expressed at sites of inflammation and produces pro-inflammatory eicosanoids. For this reason, COX-2 selective inhibitors (COXIBs) have been developed recently as anti-inflammatory agents to minimize the risk of GI toxicity. Recently, some COX-2 selective inhibitors have shown adverse cardiovascular side effects, resulting in the withdrawal of rofecoxib and valdecoxib from the market. Selective inhibition of COX-2 without reducing COX-1-mediated thromboxane production could alter the balance between prostacyclin and thromboxane and promote a prothrombotic state, thereby explaining the observed COX- 2 cardiovascular risk. In this review, we describe mechanisms for the production of pro-inflammatory eicosanoid mediators contributing to inflammation and summarize promising options for the prevention of inflammatory mediator formation and the therapeutic inhibition of pain and inflammation.