title: Design, synthesis, and structure-activity relationship studies of novel 3-alkylindole derivatives as selective and highly potent myeloperoxidase inhibitors.
abstract: Due to its production of potent antimicrobial oxidants including hypochlorous acid, human myeloperoxidase (MPO) plays a critical role in innate immunity and inflammatory diseases. Thus MPO is an attractive target in drug design. (Aminoalkyl)fluoroindole derivatives were detected to be very potent MPO inhibitors; however, they also promote inhibition of the serotonin reuptake transporter (SERT) at the same concentration range. Via structure-based drug design, a new series of MPO inhibitors derived from 3-alkylindole were synthesized and their effects were assessed on MPO-mediated taurine chlorination and low-density lipoprotein oxidation as well as on inhibition of SERT. The fluoroindole compound with three carbons in the side chain and one amide group exhibited a selectivity index of 35 (Ki/IC50) with high inhibition of MPO activity (IC50 = 18 nM), whereas its effect on SERT was in the micromolar range. Structure-function relationships, mechanism of action, and safety of the molecule are discussed.
authors.affiliation: Laboratoire de Chimie Pharmaceutique Organique, Faculté de Pharmacie, Université Libre de Bruxelles, 1050 Brussels, Belgium.
authors.forename: Jalal
authors.initials: J
authors.lastname: Soubhye
authors.forename: Iyas
authors.initials: I
authors.lastname: Aldib
authors.forename: Betina
authors.initials: B
authors.lastname: Elfving
authors.forename: Michel
authors.initials: M
authors.lastname: Gelbcke
authors.forename: Paul G
authors.initials: PG
authors.lastname: Furtmüller
authors.forename: Manuel
authors.initials: M
authors.lastname: Podrecca
authors.forename: Raphaël
authors.initials: R
authors.lastname: Conotte
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Colet
authors.forename: Alexandre
authors.initials: A
authors.lastname: Rousseau
authors.forename: Florence
authors.initials: F
authors.lastname: Reye
authors.forename: Ahmad
authors.initials: A
authors.lastname: Sarakbi
authors.forename: Michel
authors.initials: M
authors.lastname: Vanhaeverbeek
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Kauffmann
authors.forename: Christian
authors.initials: C
authors.lastname: Obinger
authors.forename: Jean
authors.initials: J
authors.lastname: Nève
authors.forename: Martine
authors.initials: M
authors.lastname: Prévost
authors.forename: Karim
authors.initials: K
authors.lastname: Zouaoui Boudjeltia
authors.forename: Francois
authors.initials: F
authors.lastname: Dufrasne
authors.forename: Pierre
authors.initials: P
authors.lastname: Van Antwerpen
mesh_terms: D000818:Animals; D002264:Carboxylic Acids / Q000737:chemistry; D003460:Crystallization; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000633:toxicity; D005461:Fluorine / Q000737:chemistry; D006801:Humans; D007202:Indicators and Reagents; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D008077:Lipoproteins, LDL / Q000737:chemistry; D008297:Male; D008958:Models, Molecular; D009584:Nitrogen / Q000737:chemistry; D010084:Oxidation-Reduction; D009195:Peroxidase / Q000037:antagonists & inhibitors*; D051381:Rats; D017208:Rats, Wistar; D017367:Selective Serotonin Reuptake Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013455:Sulfur / Q000737:chemistry; D013654:Taurine / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D002264:Carboxylic Acids; D004791:Enzyme Inhibitors; D005461:Fluorine; D007202:Indicators and Reagents; D007211:Indoles; D008077:Lipoproteins, LDL; D009584:Nitrogen; D009195:Peroxidase; D017367:Selective Serotonin Reuptake Inhibitors; D013455:Sulfur; D013654:Taurine; C043410:N-chlorotaurine