Discovery and structure-activity relationship of 1,3-cyclohexyl amide derivatives as novel mGluR5 negative allosteric modulators.
A novel series of trans-1,3-cyclohexyl diamides was discovered and characterized as mGluR5 negative allosteric modulators (NAMs) lacking an alkyne moiety. Conformational constraint of one of the amide bonds in the diamide template led to a spirooxazoline template. A representative compound (24d) showed good in vitro potency, high CNS penetration and, upon subcutaneous dosing, demonstrated efficacy in the mouse marble burying test, generally used as indicative of potential anxiolytic activity.
Discovery Chemistry & DMPK, Lundbeck Research USA, 215 College Road, Paramus, NJ 07652, USA.
Hao
H
Zhou
Sidney W
SW
Topiol
Michel
M
Grenon
Hermogenes N
HN
Jimenez
Michelle A
MA
Uberti
Daniel G
DG
Smith
Robbin M
RM
Brodbeck
Gamini
G
Chandrasena
Henrik
H
Pedersen
Jens Christian
JC
Madsen
Darío
D
Doller
Guiying
G
Li
D000494:Allosteric Regulation; D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D003510:Cyclohexanes / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D008968:Molecular Conformation; D064529:Receptor, Metabotropic Glutamate 5 / Q000737:chemistry* / Q000378:metabolism; D013329:Structure-Activity Relationship
D000577:Amides; D003510:Cyclohexanes; D064529:Receptor, Metabotropic Glutamate 5