Synthesis and biological evaluation of fenobam analogs as mGlu5 receptor antagonists.
Optimization of affinity and microsomal stability led to identification of the potent, metabolically stable fenobam analog 4l. Robust in vivo efficacy of 4l was demonstrated in four different models of anxiety. Additionally, a ligand based pharmacophore alignment of fenobam and MPEP is proposed.
Jaeschke
Georg
G
Pharmaceutical Division, Discovery Research, F. Hoffmann-La Roche Ltd, CH-4070 Basel, Switzerland. georg.jaeschke@roche.com
Porter
Richard
R
Büttelmann
Bernd
B
Ceccarelli
Simona M
SM
Guba
Wolfgang
W
Kuhn
Bernd
B
Kolczewski
Sabine
S
Huwyler
Jörg
J
Mutel
Vincent
V
Peters
Jens-Uwe
JU
Ballard
Theresa
T
Prinssen
Eric
E
Vieira
Eric
E
Wichmann
Jürgen
J
Spooren
Will
W
D000818:Animals; D014151:Anti-Anxiety Agents / Q000138:chemical synthesis; D015195:Drug Design; D006801:Humans; D007093:Imidazoles / Q000737:chemistry* / Q000494:pharmacology*; D008024:Ligands; D011725:Pyridines / Q000737:chemistry; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
D014151:Anti-Anxiety Agents; D007093:Imidazoles; D008024:Ligands; D011725:Pyridines; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; C032794:fenobam; C121465:6-methyl-2-(phenylethynyl)pyridine