Design, Synthesis, and Structure鈥揂ctivity Relationship Studies of Novel 3-Alkylindole Derivatives as Selective and Highly Potent Myeloperoxidase Inhibitors

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• 作者：Jalal Soubhye ; Iyas Aldib ; Betina Elfving ; Michel Gelbcke ; Paul G. Furtm眉ller ; Manuel Podrecca ; Rapha毛l Conotte ; Jean-Marie Colet ; Alexandre Rousseau ; Florence Reye ; Ahmad Sarakbi ; Michel Vanhaeverbeek ; Jean-Michel Kauffmann ; Christian Obinger ; Jean N猫ve ; Martine Pr茅vost ; Karim Zouaoui Boudjeltia ; Francois Dufrasne ; Pierre Van Antwerpen
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：May 23, 2013
• 年：2013
• 卷：56
• 期：10
• 页码：3943-3958
• 全文大小：701K
• 年卷期：v.56,no.10(May 23, 2013)
• ISSN：1520-4804

文摘

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 (K_i/IC₅₀) with high inhibition of MPO activity (IC₅₀ = 18 nM), whereas its effect on SERT was in the micromolar range. Structure鈥揻unction relationships, mechanism of action, and safety of the molecule are discussed.