4-Aryl-3-arylsulfonyl-quinolines as negative allosteric modulators of metabotropic GluR5 receptors: From HTS hit to development candidate

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• 作者：Já ; nos Galambos^a ; ^{J.Galambos@richter.hu" class="auth_mail" title="E-mail the corresponding author} ; Gy&ouml ; rgy Domá ; ny^a ; Katalin Nó ; grá ; di^a ; Gá ; bor Wá ; gner^b ; Gy&ouml ; rgy M. Keserű^c ; Amrita Bobok^a ; Sá ; ndor Kolok^a ; Mó ; nika L. Mikó ; -Bakk^a ; Mó ; nika Vastag^a ; Katalin Sá ; ghy^a ; Já ; nos Kó ; ti^a ; Zoltá ; n Szaká ; cs^a ; Zoltá ; n Bé ; ni^a ; Krisztina Gá ; l^a ; Zsolt Szombathelyi^a ; Istvá ; n Greiner^a
• 关键词：mGluR5 ; Negative allosteric modulator ; 4-Aryl-3-arylsulfonyl-quinolines
• 刊名：Bioorganic & Medicinal Chemistry Letters
• 出版年：2016
• 出版时间：15 February 2016
• 年：2016
• 卷：26
• 期：4
• 页码：1249-1252
• 全文大小：650 K

文摘

High throughput screening of our corporate compound library followed by hit-to-lead development resulted in a 4-aryl-3-arylsulfonyl-quinoline derivative lead (2) with mGluR5 negative allosteric modulator activity. During the lead optimization process, our objective was to improve affinity and metabolic stability. Modifications at the three targeted regions of the lead structure resulted in compounds with nanomolar affinity and acceptable metabolic stability. One of the most promising compounds (3), showing excellent in vivo efficacy, was selected for preclinical development and subsequent phase I clinical studies.