title: Synthesis and biological evaluation of C(5)-substituted derivatives of leukotriene biosynthesis inhibitor BRP-7.
abstract: Pharmacological intervention with 5-lipoxygenase (5-LO) pathway leading to suppression of leukotriene (LT) biosynthesis is a clinically validated strategy for treatment of respiratory and cardiovascular diseases such as asthma and atherosclerosis. Here we describe the synthesis of a series of C(5)-substituted analogues of the previously described 5-LO-activating protein (FLAP) inhibitor BRP-7 (IC50 = 0.31 μM) to explore the effects of substitution at the C(5)-benzimidazole (BI) ring as a strategy to increase the potency against FLAP-mediated 5-LO product formation. Incorporation of polar substituents on the C(5) position of the BI core, exemplified by compound 11 with a C(5)-nitrile substituent, significantly enhances the potency for suppression of 5-LO product synthesis in human neutrophils (IC50 = 0.07 μM) and monocytes (IC50 = 0.026 μM).
authors.affiliation: Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Gazi University, Yenimahalle, 06330 Ankara, Turkey.
authors.forename: Serkan
authors.initials: S
authors.lastname: Levent
authors.affiliation: Chair of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich-Schiller-University Jena, Philosophenweg 14, D-07743 Jena, Germany.
authors.forename: Jana
authors.initials: J
authors.lastname: Gerstmeier
authors.affiliation: Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Gazi University, Yenimahalle, 06330 Ankara, Turkey.
authors.forename: Abdurrahman
authors.initials: A
authors.lastname: Olgaç
authors.affiliation: Chair of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich-Schiller-University Jena, Philosophenweg 14, D-07743 Jena, Germany.
authors.forename: Felix
authors.initials: F
authors.lastname: Nikels
authors.affiliation: Chair of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich-Schiller-University Jena, Philosophenweg 14, D-07743 Jena, Germany.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Garscha
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Università di Perugia, Via del Liceo 1, 06123 Perugia, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Carotti
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Università di Perugia, Via del Liceo 1, 06123 Perugia, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Macchiarulo
authors.affiliation: Chair of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich-Schiller-University Jena, Philosophenweg 14, D-07743 Jena, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Werz
authors.affiliation: Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Gazi University, Yenimahalle, 06330 Ankara, Turkey. Electronic address: banoglu@gazi.edu.tr.
authors.forename: Erden
authors.initials: E
authors.lastname: Banoglu
authors.affiliation: Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Gazi University, Yenimahalle, 06330 Ankara, Turkey. Electronic address: bcaliskan@gazi.edu.tr.
authors.forename: Burcu
authors.initials: B
authors.lastname: Çalışkan
mesh_terms: D058946:5-Lipoxygenase-Activating Protein Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D058927:5-Lipoxygenase-Activating Proteins / Q000737:chemistry / Q000378:metabolism; D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism; D001562:Benzimidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D060326:Chemistry Techniques, Synthetic; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D015289:Leukotrienes / Q000096:biosynthesis*; D062105:Molecular Docking Simulation; D011487:Protein Conformation; D013329:Structure-Activity Relationship
chemical_list: C000594600:1-(2-chlorobenzyl)-2-(1-(4-isobutylphenyl)ethyl)-1H-benzimidazole; D058946:5-Lipoxygenase-Activating Protein Inhibitors; D058927:5-Lipoxygenase-Activating Proteins; D001562:Benzimidazoles; D015289:Leukotrienes; D001094:Arachidonate 5-Lipoxygenase
keywords: 5-Lipoxygenase-activating protein; BRP-7; Benzimidazole; FLAP; Leukotriene