Discovery of 1,5-disubstituted pyridones: a new class of positive allosteric modulators of the metabotropic glutamate 2 receptor.
A series of 1,5-disubstituted pyridones was identified as positive allosteric modulators (PAMs) of the metabotropic glutamate receptor 2 (mGluR2) via high throughput screening (HTS). Subsequent SAR exploration led to the identification of several compounds with improved in vitro activity. Lead compound 8 was further profiled and found to attenuate the increase in PCP induced locomotor activity in mice.
Neuroscience Medicinal Chemistry, Johnson & Johnson Pharmaceutical Research & Development, Janssen-Cilag S.A., Calle Jarama 75, Polígono Industrial, Toledo 45007, Spain.
Jose María
JM
Cid
Guillaume
G
Duvey
Philippe
P
Cluzeau
Vanthea
V
Nhem
Karim
K
Macary
Alexandre
A
Raux
Nicolas
N
Poirier
Jessica
J
Muller
Christelle
C
Boléa
Terry
T
Finn
Sonia
S
Poli
Mark
M
Epping-Jordan
Emilie
E
Chamelot
Francis
F
Derouet
Francoise
F
Girard
Gregor J
GJ
Macdonald
Juan Antonio
JA
Vega
Ana Isabel
AI
de Lucas
Encarnación
E
Matesanz
Hilde
H
Lavreysen
María Lourdes
ML
Linares
Daniel
D
Oehlrich
Julen
J
Oyarzábal
Gary
G
Tresadern
Andrés A
AA
Trabanco
Jose Ignacio
JI
Andrés
Emmanuel
E
Le Poul
Hassan
H
Imogai
Robert
R
Lutjens
Jean-Philippe
JP
Rocher
D000494:Allosteric Regulation; D000596:Amino Acids / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D001643:Bridged Bicyclo Compounds / Q000737:chemistry / Q000494:pharmacology*; D004353:Drug Evaluation, Preclinical; D004355:Drug Stability; D018690:Excitatory Amino Acid Agonists / Q000737:chemistry / Q000145:classification / Q000494:pharmacology*; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D051379:Mice; D015394:Molecular Structure; D009043:Motor Activity / Q000187:drug effects; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology*; D011728:Pyridones / Q000737:chemistry / Q000145:classification / Q000302:isolation & purification / Q000494:pharmacology*; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists*; D011994:Recombinant Proteins / Q000187:drug effects; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry / Q000494:pharmacology*
D000596:Amino Acids; D001643:Bridged Bicyclo Compounds; D018690:Excitatory Amino Acid Agonists; C534551:LY 2140023; C476436:N-(4-(2-methoxyphenoxy)phenyl)-N-(2,2,2-trifluoroethylsulfonyl)pyrid-3-ylmethylamine; D011725:Pyridines; D011728:Pyridones; D018094:Receptors, Metabotropic Glutamate; D011994:Recombinant Proteins; D013449:Sulfonamides; C108822:metabotropic glutamate receptor 2; C104753:eglumetad