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

Gábor Wágner; Csaba Wéber; Olga Nyéki; Katalin Nógrádi; Attila Bielik; László Molnár; Amrita Bobok; Attila Horváth; Béla Kiss; Sándor Kolok; József Nagy; Dalma Kurkó; Krisztina Gál; István Greiner; Zsolt Szombathelyi; György M Keseru; György Domány

doi:10.1016/j.bmcl.2010.04.075

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

Bioorg Med Chem Lett. 2010 Jun 15;20(12):3737-41. doi: 10.1016/j.bmcl.2010.04.075. Epub 2010 Apr 22.

Authors

Gábor Wágner¹, Csaba Wéber, Olga Nyéki, Katalin Nógrádi, Attila Bielik, László Molnár, Amrita Bobok, Attila Horváth, Béla Kiss, Sándor Kolok, József Nagy, Dalma Kurkó, Krisztina Gál, István Greiner, Zsolt Szombathelyi, György M Keseru, György Domány

Affiliation

¹ Gedeon Richter Plc, Budapest, Hungary. [email protected]

PMID: 20483612
DOI: 10.1016/j.bmcl.2010.04.075

Abstract

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.

MeSH terms

Allosteric Regulation / drug effects*
Animals
Drug Discovery
Humans
Ligands
Oxadiazoles / chemical synthesis*
Oxadiazoles / chemistry
Oxadiazoles / pharmacology
Receptor, Metabotropic Glutamate 5
Receptors, Metabotropic Glutamate / drug effects*
Structure-Activity Relationship
Tetrazoles / chemical synthesis*
Tetrazoles / chemistry
Tetrazoles / pharmacology

Substances

GRM5 protein, human
Ligands
Oxadiazoles
Receptor, Metabotropic Glutamate 5
Receptors, Metabotropic Glutamate
Tetrazoles