• Citer

Design, synthesis, and structure-activity relationship studies of novel 3-alkylindole derivatives as selective and highly potent myeloperoxidase inhibitors.

par Soubhye, Jalal ;Aldib, Iyas ;Elfving, Betina;Gelbcke, Michel ;Furtmüller, Paul G;Podrecca, Manuel;Conotte, Raphaël;Colet, Jean-Marie ;Rousseau, Alexandre ;Reye, Florence ;Sarakbi, Ahmad ;Vanhaeverbeek, Michel ;Kauffmann, Jean-Michel ;Obinger, Christian;Neve, Jean ;Prévost, Martine ;Zouaoui Boudjeltia, Karim ;Dufrasne, François ;Van Antwerpen, Pierre
Référence Journal of medicinal chemistry, 56, 10, page (3943-3958)
Publication Publié, 2013-05

Article révisé par les pairs

• Accès en ligne
• Détails
• Contenu
• Statistiques

Résumé :

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.