3-Benzyl-1,3-oxazolidin-2-ones as mGluR2 positive allosteric modulators: Hit-to lead and lead optimization.
The discovery, synthesis and SAR of a novel series of 3-benzyl-1,3-oxazolidin-2-ones as positive allosteric modulators (PAMs) of mGluR2 is described. Expedient hit-to-lead work on a single HTS hit led to the identification of a ligand-efficient and structurally attractive series of mGluR2 PAMs. Human microsomal clearance and suboptimal physicochemical properties of the initial lead were improved to give potent, metabolically stable and orally available mGluR2 PAMs.
Duplantier
Allen J
AJ
CNS Chemistry, Pfizer Global Research and Development, Eastern Point Road, Groton, CT 06340, USA.
Efremov
Ivan
I
Candler
John
J
Doran
Angela C
AC
Ganong
Alan H
AH
Haas
Jessica A
JA
Hanks
Ashley N
AN
Kraus
Kenneth G
KG
Lazzaro
John T
JT
Lu
Jiemin
J
Maklad
Noha
N
McCarthy
Sheryl A
SA
O'Sullivan
Theresa J
TJ
Rogers
Bruce N
BN
Siuciak
Judith A
JA
Spracklin
Douglas K
DK
Zhang
Lei
L