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

[Display omitted] 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 a...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2016-02, Vol.26 (4), p.1249-1252
Main Authors: Galambos, János, Domány, György, Nógrádi, Katalin, Wágner, Gábor, Keserű, György M., Bobok, Amrita, Kolok, Sándor, Mikó-Bakk, Mónika L., Vastag, Mónika, Sághy, Katalin, Kóti, János, Szakács, Zoltán, Béni, Zoltán, Gál, Krisztina, Szombathelyi, Zsolt, Greiner, István
Format: Article
Language:English
Subjects:
4-Aryl-3-arylsulfonyl-quinolines
Allosteric Regulation
Animals
Central Nervous System Diseases - etiology
High-Throughput Screening Assays
Humans
mGluR5
Negative allosteric modulator
Protein Binding
Quinolines - chemical synthesis
Quinolines - chemistry
Quinolines - metabolism
Quinolines - toxicity
Rats
Receptor, Metabotropic Glutamate 5 - chemistry
Receptor, Metabotropic Glutamate 5 - metabolism
Structure-Activity Relationship
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Summary:[Display omitted] 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.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2016.01.024