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

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

  • Bioorg Med Chem Lett. 2016 Feb 15;26(4):1249-52. doi: 10.1016/j.bmcl.2016.01.024.
János Galambos 1,  György Domány 2,  Katalin Nógrádi 2,  Gábor Wágner 3,  György M Keserű 4,  Amrita Bobok 2,  Sándor Kolok 2,  Mónika L Mikó-Bakk 2,  Mónika Vastag 2,  Katalin Sághy 2,  János Kóti 2,  Zoltán Szakács 2,  Zoltán Béni 2,  Krisztina Gál 2,  Zsolt Szombathelyi 2,  István Greiner 2
Affiliations

Affiliations

  • 1 Gedeon Richter Plc, Budapest 10, PO Box 27, H-1475, Hungary. Electronic address: J.Galambos@richter.hu.
  • 2 Gedeon Richter Plc, Budapest 10, PO Box 27, H-1475, Hungary.
  • 3 Division of Medicinal Chemistry, Amsterdam Institute for Molecules Medicines and Systems, VU University Amsterdam, De Boelelaan 1083, 1081 HV Amsterdam, The Netherlands.
  • 4 Research Centre for Natural Sciences, Hungarian Academy of Sciences, Magyar tudósok krt. 2, H-1117 Budapest, Hungary.
PMID: 26774652 DOI: 10.1016/j.bmcl.2016.01.024
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.

Keywords

4-Aryl-3-arylsulfonyl-quinolines; Negative allosteric modulator; mGluR5.

Figures