Arylmethoxypyridines as novel, potent and orally active mGlu5 receptor antagonists.
Optimisation of affinity, chemical stability, metabolic stability and solubility led from a chemically labile HTS hit 1 to mGlu5 receptor antagonists (24-26) with high affinity for the allosteric MPEP binding site, improved microsomal metabolic stability and anxiolytic-like activity in vivo as assessed by the Vogel conflict drinking test.
Büttelmann
Bernd
B
Pharma Division, Discovery Chemistry, F. Hoffman-La Roche Ltd, CH-4070 Basel, Switzerland.
Peters
Jens-Uwe
JU
Ceccarelli
Simona
S
Kolczewski
Sabine
S
Vieira
Eric
E
Prinssen
Eric P
EP
Spooren
Will
W
Schuler
Franz
F
Huwyler
Jörg
J
Porter
Richard H P
RH
Jaeschke
Georg
G
D000284:Administration, Oral; D018691:Excitatory Amino Acid Antagonists / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D011725:Pyridines / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors*
D018691:Excitatory Amino Acid Antagonists; D011725:Pyridines; D018094:Receptors, Metabotropic Glutamate