Hit-to-lead optimization of disubstituted oxadiazoles and tetrazoles as mGluR5 NAMs

Hit-to-lead optimization of disubstituted oxadiazoles and tetrazoles as mGluR5 NAMs

Here we report the discovery and early SAR of a series of mGluR5 negative allosteric modulators (NAMs). Starting from a moderately active HTS hit we synthesized 3,5-disubstituted-oxadiazoles and tetrazoles as mGluR5 NAMs. Based on the analysis of ligand efficiency and lipophilic efficiency metrics w...

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Veröffentlicht in:Bioorganic & medicinal chemistry letters 2010-06, Vol.20 (12), p.3737-3741
Hauptverfasser: Wágner, Gábor, Wéber, Csaba, Nyéki, Olga, Nógrádi, Katalin, Bielik, Attila, Molnár, László, Bobok, Amrita, Horváth, Attila, Kiss, Béla, Kolok, Sándor, Nagy, József, Kurkó, Dalma, Gál, Krisztina, Greiner, István, Szombathelyi, Zsolt, Keserű, György M., Domány, György
Format: Artikel
Sprache:eng
Schlagworte:
Allosteric Regulation - drug effects
Animals
Drug Discovery
Humans
Ligands
mGluR5
Negative allosteric modulator
Oxadiazoles - chemical synthesis
Oxadiazoles - chemistry
Oxadiazoles - pharmacology
Parallel synthesis
Receptor, Metabotropic Glutamate 5
Receptors, Metabotropic Glutamate - drug effects
Structure-Activity Relationship
Tetrazoles - chemical synthesis
Tetrazoles - chemistry
Tetrazoles - pharmacology
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Zusammenfassung:Here we report the discovery and early SAR of a series of mGluR5 negative allosteric modulators (NAMs). Starting from a moderately active HTS hit we synthesized 3,5-disubstituted-oxadiazoles and tetrazoles as mGluR5 NAMs. Based on the analysis of ligand efficiency and lipophilic efficiency metrics we identified a promising lead candidate as a starting point for further optimization.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2010.04.075