3-Aryl-5-phenoxymethyl-1,3-oxazolidin-2-ones as positive allosteric modulators of mGluR2 for the treatment of schizophrenia: Hit-to-lead efforts.
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.
Brnardic
Edward J
EJ
Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA. edward_brnardic@merck.com
Fraley
Mark E
ME
Garbaccio
Robert M
RM
Layton
Mark E
ME
Sanders
John M
JM
Culberson
Chris
C
Jacobson
Marlene A
MA
Magliaro
Brian C
BC
Hutson
Pete H
PH
O'Brien
Julie A
JA
Huszar
Sarah L
SL
Uslaner
Jason M
JM
Fillgrove
Kerry L
KL
Tang
Cuyue
C
Kuo
Yuhsin
Y
Sur
Sylvie M
SM
Hartman
George D
GD
D000494:Allosteric Regulation; D000818:Animals; D014150:Antipsychotic Agents; D007649:Ketamine / Q000633:toxicity; D023303:Oxazolidinones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D051381:Rats; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists / Q000378:metabolism*; D012559:Schizophrenia / Q000188:drug therapy*; D013329:Structure-Activity Relationship
D014150:Antipsychotic Agents; D023303:Oxazolidinones; D018094:Receptors, Metabotropic Glutamate; C108822:metabotropic glutamate receptor 2; D007649:Ketamine