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

Index: J. Med. Chem. 56(10) , 3943-58, (2013)

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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.