4-aryl piperazine and piperidine amides as novel mGluR5 positive allosteric modulators

  • Bioorg Med Chem Lett. 2010 Dec 15;20(24):7381-4. doi: 10.1016/j.bmcl.2010.10.036.
Hui Xiong  1 ,  Todd A Brugel ,  Michael Balestra ,  Dean G Brown ,  Kelly A Brush ,  Caprice Hightower ,  Lindsay Hinkley ,  Valerie Hoesch ,  James Kang ,  Gerard M Koether ,  John P McCauley Jr ,  Francis M McLaren ,  Laura M Panko ,  Thomas R Simpson ,  Reed W Smith ,  James M Woods ,  Becky Brockel ,  Vijay Chhajlani ,  Reto A Gadient ,  Nathan Spear ,  Linda A Sygowski ,  Minli Zhang ,  Jalaj Arora ,  Nathalie Breysse ,  Julie M Wilson ,  Methvin Isaac ,  Abdelmalik Slassi ,  Megan M King
Affiliations
PMID: 21067920 DOI: 10.1016/j.bmcl.2010.10.036
Abstract

Positive allosteric modulation of metabotropic glutamate receptor 5 (mGluR5) is regarded as a potential novel treatment for schizophrenic patients. Herein we report the synthesis and SAR of 4-aryl piperazine and piperidine amides as potent mGluR5 positive allosteric modulators (PAMs). Several analogs have excellent activity and desired drug-like properties. Compound 2b was further characterized as a PAM using several in vitro experiments, and produced robust activity in several preclinical animal models.