3-Cyano-5-fluoro-N-arylbenzamides as negative allosteric modulators of mGlu5: Identification of easily prepared tool compounds with CNS exposure in rats

doi:10.1016/j.bmcl.2010.06.064

Bioorganic & Medicinal Chemistry Letters

Volume 20, Issue 15, 1 August 2010, Pages 4390-4394

https://doi.org/10.1016/j.bmcl.2010.06.064 Get rights and content

Abstract

Development of SAR in a 3-cyano-5-fluoro-N-arylbenzamide series of non-competitive antagonists of mGlu₅ using a functional cell-based assay is described in this Letter. Further characterization of selected potent compounds in in vitro assays designed to measure their metabolic stability and protein binding is also presented. Subsequent evaluation of two new compounds in pharmacokinetic studies using intraperitoneal dosing in rats demonstrated good exposure in both plasma and brain samples.

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Acknowledgments

We thank NIDA (RO1 DA023947-01) and Seaside Therapeutics (VUMC33842) for their support of our programs in the development of non-competitive antagonist of mGlu₅. Matt Mulder, Chris Denicola, and Sichen Chang are also thanked for the purification of compounds using the mass-directed HPLC system.

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3-Cyano-5-fluoro-N-arylbenzamides as negative allosteric modulators of mGlu5: Identification of easily prepared tool compounds with CNS exposure in rats

Abstract

Graphical abstract

Section snippets

Acknowledgments

Neuropharmacology

Annu. Rev. Pharmacol. Toxicol.

J. Med. Chem.

Eur. J. Pharmacol.

Eur. J. Pharmacol.

Gastroenterology

Neurobiol. Dis.

Neuropharmacology

J. Pharmacol. Exp. Ther.

Behav. Brain Res.

Neuropsychopharmacology

J. Med. Chem.

Psychopharmacology

Eur. J. Pharmacol.

Eur. J. Pharmacol.

Neuropsychopharmacology

J. Neurosci.

Neuropharmacology

Drug Alcohol Depend.

Gut

Synapse

Bioorg. Med. Chem. Lett.

Basic Clin. Pharmacol. Toxicol.

Pharmacol. Ther.

Neuropharmacology

3-Cyano-5-fluoro-N-arylbenzamides as negative allosteric modulators of mGlu₅: Identification of easily prepared tool compounds with CNS exposure in rats