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

János Galambos*, György Domány, Katalin Nógrádi, Gábor Wágner, György M. Keseru, Amrita Bobok, Sándor Kolok, Mónika L. Mikó-Bakk, Mónika Vastag, Katalin Sághy, János Kóti, Zoltán Szakács, Zoltán Béni, Krisztina Gál, Zsolt Szombathelyi, István Greiner

*Corresponding author for this work

Research output: Contribution to JournalArticleAcademicpeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)1249-1252
Number of pages4
JournalBioorganic and Medicinal Chemistry Letters
Volume26
Issue number4
DOIs
Publication statusPublished - 15 Feb 2016

Keywords

  • 4-Aryl-3-arylsulfonyl-quinolines
  • mGluR5
  • Negative allosteric modulator

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