Piperidyl amides as novel, potent and orally active mGlu5 receptor antagonists with anxiolytic-like activity.
High throughput screening led to the identification of nicotinamide derivative 2 as a structurally novel mGluR5 antagonist. Optimization of the modular scaffold led to the discovery of 16m, a compound with high affinity for mGluR5 and excellent selectivity over other glutamate receptors. Compound 16m exhibits a favorable PK profile in rats, robust anxiolytic-like effects in three different animal models of fear and anxiety, as well as a good PK/PD correlation.
Spanka
Carsten
C
Novartis Institutes for Biomedical Research, Global Discovery Chemistry, Basel CH-4002, Switzerland.
Glatthar
Ralf
R
Desrayaud
Sandrine
S
Fendt
Markus
M
Orain
David
D
Troxler
Thomas
T
Vranesic
Ivo
I
D000284:Administration, Oral; D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D000631:Aminopyridines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D000818:Animals; D014151:Anti-Anxiety Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D006801:Humans; D008862:Microsomes, Liver / Q000378:metabolism; D010455:Peptides / Q000737:chemistry*; D051381:Rats; D017207:Rats, Sprague-Dawley; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
D000577:Amides; D000631:Aminopyridines; D014151:Anti-Anxiety Agents; C578935:GRM5 protein, human; C578937:Grm5 protein, rat; D010455:Peptides; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate