Discovery of a potent and brain penetrant mGluR5 positive allosteric modulator.
This Letter describes the discovery of a novel series of mGluR5 positive allosteric modulators (PAMs). The lead compound, 11c, exhibits excellent potency (EC(50)=30 nM) in vitro, and reaches high brain levels in both rats and mice after oral administration.
Ritzén
Andreas
A
Medicinal Chemistry Research DK, H. Lundbeck A/S, Ottiliavej 9, DK-2500 Valby, Denmark. arit@lundbeck.com
Sindet
Rikke
R
Hentzer
Morten
M
Svendsen
Nannette
N
Brodbeck
Robbin M
RM
Bundgaard
Christoffer
C
D000284:Administration, Oral; D000480:Alkynes / Q000737:chemistry* / Q000494:pharmacology; D000494:Allosteric Regulation; D000818:Animals; D001921:Brain / Q000378:metabolism*; D055808:Drug Discovery; D006571:Heterocyclic Compounds / Q000737:chemistry* / Q000494:pharmacology; D051379:Mice; D051381:Rats; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists*; D013329:Structure-Activity Relationship
D000480:Alkynes; C578936:Grm5 protein, mouse; C578937:Grm5 protein, rat; D006571:Heterocyclic Compounds; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate