4-aryl piperazine and piperidine amides as novel mGluR5 positive allosteric modulators.
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.
CNS Discovery, AstraZeneca Pharmaceuticals, Wilmington, DE, USA. hui.xiong@astrazeneca.com
Hui
H
Xiong
Todd A
TA
Brugel
Michael
M
Balestra
Dean G
DG
Brown
Kelly A
KA
Brush
Caprice
C
Hightower
Lindsay
L
Hinkley
Valerie
V
Hoesch
James
J
Kang
Gerard M
GM
Koether
John P
JP
McCauley
Francis M
FM
McLaren
Laura M
LM
Panko
Thomas R
TR
Simpson
Reed W
RW
Smith
James M
JM
Woods
Becky
B
Brockel
Vijay
V
Chhajlani
Reto A
RA
Gadient
Nathan
N
Spear
Linda A
LA
Sygowski
Minli
M
Zhang
Jalaj
J
Arora
Nathalie
N
Breysse
Julie M
JM
Wilson
Methvin
M
Isaac
Abdelmalik
A
Slassi
Megan M
MM
King
D000494:Allosteric Regulation; D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use; D006801:Humans; D008862:Microsomes, Liver / Q000378:metabolism; D000077489:Piperazine; D010879:Piperazines / Q000737:chemistry*; D010880:Piperidines / Q000737:chemistry*; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000737:chemistry* / Q000378:metabolism; D012559:Schizophrenia / Q000188:drug therapy; D013329:Structure-Activity Relationship
D000577:Amides; C578935:GRM5 protein, human; D010879:Piperazines; D010880:Piperidines; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; D000077489:Piperazine; C032727:piperidine