title: Novel leukotriene biosynthesis inhibitors (2012-2016) as anti-inflammatory agents.
abstract: 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), LTA4hydrolase and LTC4synthase 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, LTA4hydrolase and LTC4synthase, 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 LTA4hydrolase and LTC4synthase 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.
authors.affiliation: a Department of Pharmaceutical/Medicinal Chemistry , Institute of Pharmacy, Friedrich-Schiller-University Jena , Jena , Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Werz
authors.affiliation: a Department of Pharmaceutical/Medicinal Chemistry , Institute of Pharmacy, Friedrich-Schiller-University Jena , Jena , Germany.
authors.forename: Jana
authors.initials: J
authors.lastname: Gerstmeier
authors.affiliation: a Department of Pharmaceutical/Medicinal Chemistry , Institute of Pharmacy, Friedrich-Schiller-University Jena , Jena , Germany.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Garscha
mesh_terms: D058946:5-Lipoxygenase-Activating Protein Inhibitors / Q000494:pharmacology; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D015195:Drug Design; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors; D005982:Glutathione Transferase / Q000037:antagonists & inhibitors; D006801:Humans; D007249:Inflammation / Q000188:drug therapy* / Q000473:pathology; D015289:Leukotrienes / Q000096:biosynthesis / Q000378:metabolism*; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology; D010330:Patents as Topic
chemical_list: D058946:5-Lipoxygenase-Activating Protein Inhibitors; D000893:Anti-Inflammatory Agents; D015289:Leukotrienes; D016859:Lipoxygenase Inhibitors; D005982:Glutathione Transferase; D004851:Epoxide Hydrolases; C041116:leukotriene-C4 synthase; C043134:leukotriene A4 hydrolase
keywords: 5-lipoxygenase; 5-lipoxygenase-activating protein; Inflammation; leukotriene; leukotriene A4 hydrolase; leukotriene C4 synthase