Recent Advances in the Search for Novel 5‐Lipoxygenase Inhibitors

Abstract

5-Lipoxygenase (5-LO) is an important enzyme of the arachidonic acid cascade and catalyses with the help of FLAP, the 5-LO-activating protein, the formation of bioactive leukotrienes (LTs). LTs are inflammatory mediators playing a pathophysiological role in different diseases such as asthma, allergic rhinitis as well as cardiovascular diseases and certain types of cancer. Up to now, only one 5-LO inhibitor is on the market, zileuton for the treatment of asthma. With the rising number of indications for anti-LT therapy, 5-LO inhibitor drug development becomes more and more important. This MiniReview gives an update on 5-LO inhibitors currently under clinical development. Furthermore, the recent advances in the search for novel 5-lipoxygenase inhibitors with a focus on computational methods are summarized. Currently, licofelone is the compound with the highest clinical development status (completed phase III trials). 5-LO inhibitor screening programmes based on computational methods could deliver several promising drug-like new molecules. These activities can be expected to be driven by the newly resolved structure of human 5-LO in the future, enabling structure-based drug design. For the prospective drugs in late-stage clinical development, the future will show their clinical safety and efficacy in the particular diseases. The 5-LO-derived arachidonic acid metabolites have been shown to be potent mediators of inflammatory reactions. During the last decades, many investigations demonstrated that the 5-LO pathway plays a role in the development of allergic diseases such as asthma [2] Most of the 5-LO inhibitors bind to the catalytic site and show a more or less competitive inhibition of the enzyme. 5-LO inhibitors can be classified into three main groups: redoxactive compounds, iron-ligand inhibitors with weak redoxactive properties and non-redox-type inhibitors [7].Insights into the pharmacological potential of 5-LO inhibitors were obtained in studies using 5-LO-deficient mice. 5-LOdeficient mice are strongly resistant against PAF-induced shock and show reduced airway reactivity [8]. Furthermore, interference with the 5-LO pathway via blockage of FLAP was found to reduce collagen-induced arthritis [9]. Another study with 5-LO-deficient mice suggests that 5-LO plays a critical role in the development of chronic myeloid leukaemia [4].Up to now, the iron-ligand type-5-LO inhibitor zileuton is the only 5-LO inhibitor that came on the market for the treatment of asthma. So, how to come up with novel inhibitors? There are several different strategies in drug design, divided mainly in (I) the improvement of already known compounds by medicinal chemistry approaches to cope with, for example, a poor pharmacokinetic profile and (II) the identification of novel scaffolds. For the latter, high-throughput screening of large databases of synthetic compounds or natural product extracts to find active compounds can be applied. Alternatively, computational methods are quite helpful tools to speed up the drug discovery p...

Androgen-mediated sex bias impairs efficiency of leukotriene biosynthesis inhibitors in males

“…Clinically relevant LT-modifying agents include inhibitors of FLAP or 5-LO, which are currently under clinical investigation as candidates for the treatment of respiratory and cardiovascular diseases (18,19). Despite intensive research, only the direct 5-LO inhibitor zileuton entered the market as an antiasthmatic drug, while other compounds failed in clinical trials due to lack of efficacy Proinflammatory leukotrienes (LTs) are produced by 5-lipoxygenase (5-LO) aided by 5-LO-activating protein (FLAP).…”

“…), in female mice (Table 2). Taking or toxicity (19). However, either published studies did not examine sex subgroups separately or sex-related effects were not reported.…”

Antileukotriene therapy by reducing tau phosphorylation improves synaptic integrity and cognition of P301S transgenic mice

“…With this goal in mind, we chronically administered zileuton, an orally available and irreversible 5LO activation inhibitor (Steinhilber & Hofmann, 2014), to the P301S mice starting at 3 months of age. After 7 months of treatment, we found that P301S mice receiving zileuton when compared with P301S receiving vehicle displayed a significant improvement in their memory as shown in the Y‐maze paradigm, which by recording spontaneous alternation behavior assesses short‐term and working memory.…”

Investigating The Inhibition Of 5-LO Enzyme By Main Cannabinoids Contained In Cannabis Sativa And Seized Resin Cannabis By Using Molecular Modeling

“…The 5-LO-derived arachidonic acid metabolites have been shown to be potent mediators of inflammatory reactions [4]. During the last decades, many investigations demonstrated that the 5-LO pathway plays a role in the development of allergic diseases such as asthma and inflammatory disorders.…”

“…Moreover, there is some evidence that the 5-LO pathway could be involved in tumorigenesis, especially in prostate cancer and certain forms of leukaemia. Up to now, only one 5-LO inhibitor is on the market, zileuton for the treatment of asthma [4].…”