Novel leukotriene biosynthesis inhibitors (2012-2016) as anti-inflammatory agents

ABSTRACT

Introduction: Leukotrienes (LTs) are lipid mediators produced from arachidonic acid with a broad variety of bioactivities in allergy and inflammation. The biosynthesis of LTs mainly involves 5-lipoxygenase (5-LO) and its 5-lipoxygenase-activating protein (FLAP), LTA₄ hydrolase and LTC₄ synthase that all may represent potential targets for LT biosynthesis inhibitors.

Areas covered: We introduce the LT biosynthetic pathway and its cellular regulation, the diverse biological actions of LTs and their receptors, and we briefly describe the pharmacological strategies for suppression of LT formation as well as the classes of current LT biosynthesis inhibitors. The main focus is placed on the comprehensive discussion of recently reported inhibitors of 5-LO, FLAP, LTA₄ hydrolase and LTC₄ synthase, based on literature search (PubMed and Thomson Innovation Patents Searches), covering 2012–2016.

Expert opinion: Although many new series of 5-LO inhibitors have been presented without patenting, essentially by academia, novel FLAP inhibitors (many patented) are most advanced in clinical development and are apparently the focus of pharmaceutical companies. Only few novel inhibitors of LTA₄ hydrolase and LTC₄ synthase were reported. Major issues in the development of LT synthesis inhibitors are related to loss of potency in biological relevant environment, poor pharmacokinetics, lack of oral efficacy, and side effects.

KEYWORDS:

• Inflammation
• leukotriene
• leukotriene A₄ hydrolase
• leukotriene C₄ synthase
• 5-lipoxygenase
• 5-lipoxygenase-activating protein

Article highlights

• Leukotrienes (LTs) are pro-inflammatory lipid mediators that play roles in the pathophysiology of asthma, allergic and inflammatory diseases, as well as in cardiovascular disease and cancer, implying potential for anti-LT therapy.

• 5-Lipoxygenase (5-LO), 5-lipoxygenase-activating protein (FLAP), LTA₄ hydrolase and LTC₄ synthase are involved in LT formation and represent validated pharmacological targets.

• Numerous LT biosynthesis inhibitors, in particular compounds acting on 5-LO, were developed since 1982 and many reached clinical trials but only the 5-LO inhibitor zileuton has reached the market for asthma therapy.

• The pharmacological profile, the therapeutic potential and the status of novel LT biosynthesis inhibitors published and/or patented since 2012 are reviewed and critically discussed.

• From 2012 to 9/2016, more than a dozen of novel chemotypes that target 5-LO, several promising FLAP inhibitors, but only few inhibitors of LTA₄ hydrolase and LTC₄ synthase were reported.

• Current focus by pharmaceutical companies is placed on the development of FLAP inhibitors devoid of plasma protein binding with high potencies in biological environment/in vivo, and several candidates are in advanced clinical trials.

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Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

Funding was received from Deutsche Forschungsgemeinschaft, grant numbers FOR1406 and SFB1127.