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

Hui Xiong; 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

doi:10.1016/j.bmcl.2010.10.036

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. Epub 2010 Oct 21.

Affiliation

¹ CNS Discovery, AstraZeneca Pharmaceuticals, Wilmington, DE, USA. hui.xiong@astrazeneca.com

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.

MeSH terms

Allosteric Regulation
Amides / chemical synthesis
Amides / chemistry*
Amides / therapeutic use
Humans
Microsomes, Liver / metabolism
Piperazine
Piperazines / chemistry*
Piperidines / chemistry*
Receptor, Metabotropic Glutamate 5
Receptors, Metabotropic Glutamate / chemistry*
Receptors, Metabotropic Glutamate / metabolism
Schizophrenia / drug therapy
Structure-Activity Relationship

Substances

Amides
GRM5 protein, human
Piperazines
Piperidines
Receptor, Metabotropic Glutamate 5
Receptors, Metabotropic Glutamate
Piperazine
piperidine