title: Structure-based design, synthesis, and pharmacological evaluation of 3-(aminoalkyl)-5-fluoroindoles as myeloperoxidase inhibitors.
abstract: Oxidized low-density lipoproteins (LDLs) accumulate in the vascular wall and promote local inflammation, which contributes to the progression of the atheromatous plaque. The key role of myeloperoxidase (MPO) in this process is related to its ability to modify APO B-100 in the intima and at the surface of endothelial cells. A series of 3-(aminoalkyl)-5-fluoroindole analogues was designed and synthesized by exploiting the structure-based docking of 5-fluorotryptamine, a known MPO inhibitor. In vitro assays were used to study the effects of these compounds on the inhibition of MPO-mediated taurine chlorination and oxidation of LDLs. The kinetics of the interaction between the MPO redox intermediates, Compounds I and II, and these inhibitors was also investigated. The most potent molecules possessed a 4- or 5-carbon aminoalkyl side chain and no substituent on the amino group. The mode of binding of these analogues and the mechanism of inhibition is discussed with respect to the structure of MPO and its halogenation and peroxidase cycles.
authors.affiliation: Laboratoire de Chimie Pharmaceutique Organique, Faculté de Pharmacie, Université Libre de Bruxelles, Brussels, Belgium.
authors.forename: Jalal
authors.initials: J
authors.lastname: Soubhye
authors.forename: Martine
authors.initials: M
authors.lastname: Prévost
authors.forename: Pierre
authors.initials: P
authors.lastname: Van Antwerpen
authors.forename: Karim
authors.initials: K
authors.lastname: Zouaoui Boudjeltia
authors.forename: Alexandre
authors.initials: A
authors.lastname: Rousseau
authors.forename: Paul G
authors.initials: PG
authors.lastname: Furtmüller
authors.forename: Christian
authors.initials: C
authors.lastname: Obinger
authors.forename: Michel
authors.initials: M
authors.lastname: Vanhaeverbeek
authors.forename: Jean
authors.initials: J
authors.lastname: Ducobu
authors.forename: Jean
authors.initials: J
authors.lastname: Néve
authors.forename: Michel
authors.initials: M
authors.lastname: Gelbcke
authors.forename: Franc Ois
authors.initials: FO
authors.lastname: Dufrasne
mesh_terms: D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D054879:Halogenation; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007700:Kinetics; D008077:Lipoproteins, LDL / Q000737:chemistry; D008958:Models, Molecular; D010084:Oxidation-Reduction; D009195:Peroxidase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D011485:Protein Binding; D011994:Recombinant Proteins / Q000737:chemistry; D013329:Structure-Activity Relationship; D013654:Taurine / Q000378:metabolism; D013816:Thermodynamics
chemical_list: D007211:Indoles; D008077:Lipoproteins, LDL; D011994:Recombinant Proteins; D013654:Taurine; D009195:Peroxidase