title: BRP-187: A potent inhibitor of leukotriene biosynthesis that acts through impeding the dynamic 5-lipoxygenase/5-lipoxygenase-activating protein (FLAP) complex assembly.
abstract: The pro-inflammatory leukotrienes (LTs) are formed from arachidonic acid (AA) in activated leukocytes, where 5-lipoxygenase (5-LO) translocates to the nuclear envelope to assemble a functional complex with the integral nuclear membrane protein 5-LO-activating protein (FLAP). FLAP, a MAPEG family member, facilitates AA transfer to 5-LO for efficient conversion, and LT biosynthesis critically depends on FLAP. Here we show that the novel LT biosynthesis inhibitor BRP-187 prevents the 5-LO/FLAP interaction at the nuclear envelope of human leukocytes without blocking 5-LO nuclear redistribution. BRP-187 inhibited 5-LO product formation in human monocytes and polymorphonuclear leukocytes stimulated by lipopolysaccharide plus N-formyl-methionyl-leucyl-phenylalanine (IC50=7-10nM), and upon activation by ionophore A23187 (IC50=10-60nM). Excess of exogenous AA markedly impaired the potency of BRP-187. Direct 5-LO inhibition in cell-free assays was evident only at >35-fold higher concentrations, which was reversible and not improved under reducing conditions. BRP-187 prevented A23187-induced 5-LO/FLAP complex assembly in leukocytes but failed to block 5-LO nuclear translocation, features that were shared with the FLAP inhibitor MK886. Whereas AA release, cyclooxygenases and related LOs were unaffected, BRP-187 also potently inhibited microsomal prostaglandin E2synthase-1 (IC50=0.2μM), another MAPEG member. In vivo, BRP-187 (10mg/kg) exhibited significant effectiveness in zymosan-induced murine peritonitis, suppressing LT levels in peritoneal exudates as well as vascular permeability and neutrophil infiltration. Together, BRP-187 potently inhibits LT biosynthesis in vitro and in vivo, which seemingly is caused by preventing the 5-LO/FLAP complex assembly and warrants further preclinical evaluation.
authors: Chair of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich Schiller University Jena, Philosophenweg 14, D-07743 Jena, Germany. Electronic address: ulrike.garscha@uni-jena.de.
authors: Ulrike
authors: U
authors: Garscha
authors: Chair of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich Schiller University Jena, Philosophenweg 14, D-07743 Jena, Germany. Electronic address: susanna.voelker@gmx.de.
authors: Susanna
authors: S
authors: Voelker
authors: Chair of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich Schiller University Jena, Philosophenweg 14, D-07743 Jena, Germany. Electronic address: simona.pace@uni-jena.de.
authors: Simona
authors: S
authors: Pace
authors: Chair of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich Schiller University Jena, Philosophenweg 14, D-07743 Jena, Germany. Electronic address: jana.gerstmeier@uni-jena.de.
authors: Jana
authors: J
authors: Gerstmeier
authors: Chair of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich Schiller University Jena, Philosophenweg 14, D-07743 Jena, Germany. Electronic address: eminibesa@gmail.com.
authors: Besa
authors: B
authors: Emini
authors: Chair of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich Schiller University Jena, Philosophenweg 14, D-07743 Jena, Germany. Electronic address: stefanie.liening@uni-jena.de.
authors: Stefanie
authors: S
authors: Liening
authors: Department of Pharmacy, University of Naples Federico II, 80131 Naples, Italy. Electronic address: antrossi@unina.it.
authors: Antonietta
authors: A
authors: Rossi
authors: Institute of Transfusion Medicine, University Hospital Jena, 07743 Jena, Germany. Electronic address: christina.weinigel@med.uni-jena.de.
authors: Christina
authors: C
authors: Weinigel
authors: Institute of Transfusion Medicine, University Hospital Jena, 07743 Jena, Germany. Electronic address: silke.rummler@med.uni-jena.de.
authors: Silke
authors: S
authors: Rummler
authors: Jena Center for Soft Matter (JCSM), Friedrich Schiller University Jena, Philosophenweg 7, 07743 Jena, Germany; Laboratory of Organic and Macromolecular Chemistry (IOMC), Friedrich Schiller University Jena, Humboldtstrasse 10, D-07743 Jena, Germany. Electronic address: ulrich.schubert@uni-jena.de.
authors: Ulrich S
authors: US
authors: Schubert
authors: Chair of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich Schiller University Jena, Philosophenweg 14, D-07743 Jena, Germany. Electronic address: gerhard.scriba@uni-jena.de.
authors: Gerhard K E
authors: GK
authors: Scriba
authors: Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Gazi University, Etiler, 06330 Yenimahalle, Ankara, Turkey. Electronic address: ersancelikoglu@gmail.com.
authors: Erşan
authors: E
authors: Çelikoğlu
authors: Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Gazi University, Etiler, 06330 Yenimahalle, Ankara, Turkey. Electronic address: brcaliskan@gmail.com.
authors: Burcu
authors: B
authors: Çalışkan
authors: Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Gazi University, Etiler, 06330 Yenimahalle, Ankara, Turkey. Electronic address: banoglu@gazi.edu.tr.
authors: Erden
authors: E
authors: Banoglu
authors: Department of Pharmacy, University of Naples Federico II, 80131 Naples, Italy. Electronic address: sautebin@unina.it.
authors: Lidia
authors: L
authors: Sautebin
authors: Chair of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich Schiller University Jena, Philosophenweg 14, D-07743 Jena, Germany; Jena Center for Soft Matter (JCSM), Friedrich Schiller University Jena, Philosophenweg 7, 07743 Jena, Germany. Electronic address: oliver.werz@uni-jena.de.
authors: Oliver
authors: O
authors: Werz
mesh_terms: D058927:5-Lipoxygenase-Activating Proteins / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000235:genetics / Q000378:metabolism*; D002474:Cell-Free System; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D057809:HEK293 Cells; D006801:Humans; D006918:Hydroxyurea / Q000031:analogs & derivatives / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D007555:Isoxazoles / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D020024:Leukotriene Antagonists / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D015289:Leukotrienes / Q000096:biosynthesis*; D008297:Male; D051379:Mice; D015394:Molecular Structure; D010538:Peritonitis / Q000139:chemically induced / Q000188:drug therapy; D011804:Quinolines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D015054:Zymosan / Q000633:toxicity; D002722:Chlorobenzenes
chemical_list: D058927:5-Lipoxygenase-Activating Proteins; D001094:Arachidonate 5-Lipoxygenase; D006918:Hydroxyurea; D007211:Indoles; D007555:Isoxazoles; D020024:Leukotriene Antagonists; D015289:Leukotrienes; D011804:Quinolines; D015054:Zymosan; C000618345:BRP-187; C060893:MK-886; D002722:Chlorobenzenes; C063449:zileuton
keywords: 5-Lipoxygenase; 5-Lipoxygenase-activating protein; Arachidonic acid; Inflammation; Leukotriene