3-Aryl-5-phenoxymethyl-1,3-oxazolidin-2-ones as positive allosteric modulators of mGluR2 for the treatment of schizophrenia: Hit-to-lead efforts

Edward J Brnardic; Mark E Fraley; Robert M Garbaccio; Mark E Layton; John M Sanders; Chris Culberson; Marlene A Jacobson; Brian C Magliaro; Pete H Hutson; Julie A O'Brien; Sarah L Huszar; Jason M Uslaner; Kerry L Fillgrove; Cuyue Tang; Yuhsin Kuo; Sylvie M Sur; George D Hartman

doi:10.1016/j.bmcl.2010.03.089

3-Aryl-5-phenoxymethyl-1,3-oxazolidin-2-ones as positive allosteric modulators of mGluR2 for the treatment of schizophrenia: Hit-to-lead efforts

Bioorg Med Chem Lett. 2010 May 15;20(10):3129-33. doi: 10.1016/j.bmcl.2010.03.089. Epub 2010 Mar 31.

Authors

Edward J Brnardic¹, Mark E Fraley, Robert M Garbaccio, Mark E Layton, John M Sanders, Chris Culberson, Marlene A Jacobson, Brian C Magliaro, Pete H Hutson, Julie A O'Brien, Sarah L Huszar, Jason M Uslaner, Kerry L Fillgrove, Cuyue Tang, Yuhsin Kuo, Sylvie M Sur, George D Hartman

Affiliation

¹ Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA. edward_brnardic@merck.com

PMID: 20409708
DOI: 10.1016/j.bmcl.2010.03.089

Abstract

Hit to lead optimization of (5R)-5-hexyl-3-phenyl-1,3-oxazolidin-2-one as a positive allosteric modulator of mGluR2 is described. Improvements in potency and metabolic stability were achieved through SAR on both ends of the oxazolidinone. An optimized lead compound was found to be brain penetrant and active in a rat ketamine-induced hyperlocomotion model for antipsychotic activity.

MeSH terms

Allosteric Regulation
Animals
Antipsychotic Agents
Ketamine / toxicity
Oxazolidinones / chemical synthesis
Oxazolidinones / chemistry*
Oxazolidinones / pharmacology
Rats
Receptors, Metabotropic Glutamate / agonists
Receptors, Metabotropic Glutamate / metabolism*
Schizophrenia / drug therapy*
Structure-Activity Relationship

Substances

Antipsychotic Agents
Oxazolidinones
Receptors, Metabotropic Glutamate
metabotropic glutamate receptor 2
Ketamine