Journal of medicinal and pharmaceutical chemistry 2013-05-23
Design, synthesis, and structure-activity relationship studies of novel 3-alkylindole derivatives as selective and highly potent myeloperoxidase inhibitors.
Jalal Soubhye, Iyas Aldib, Betina Elfving, Michel Gelbcke, Paul G Furtmüller, Manuel Podrecca, Raphaël Conotte, Jean-Marie Colet, Alexandre Rousseau, Florence Reye, Ahmad Sarakbi, Michel Vanhaeverbeek, Jean-Michel Kauffmann, Christian Obinger, Jean Nève, Martine Prévost, Karim Zouaoui Boudjeltia, Francois Dufrasne, Pierre Van Antwerpen
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.
