Biphenyl-indanones: allosteric potentiators of the metabotropic glutamate subtype 2 receptor.
We have identified and synthesized a series of biphenyl-carboxylic acid indanones as allosteric potentiators of the metabotropic glutamate receptor 2. Structure-activity relationship studies directed toward improving the potency and the brain to plasma ratio of the initial lead led to the discovery of 5 and 23 (EC50=111 and 5 nM, respectively).
Bonnefous
Céline
C
Department of Medicinal Chemistry, Merck Research Laboratories, MRLSDB2, 3535 General Atomics Court, San Diego, CA 92121, USA. celine_bonnefous@yahoo.com
Vernier
Jean-Michel
JM
Hutchinson
John H
JH
Gardner
Michael F
MF
Cramer
Merryl
M
James
Joyce K
JK
Rowe
Blake A
BA
Daggett
Lorrie P
LP
Schaffhauser
Hervé
H
Kamenecka
Theodore M
TM
D000494:Allosteric Regulation; D000818:Animals; D001713:Biphenyl Compounds / Q000138:chemical synthesis* / Q000378:metabolism / Q000493:pharmacokinetics; D001923:Brain Chemistry; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D006801:Humans; D007189:Indans / Q000138:chemical synthesis* / Q000378:metabolism / Q000493:pharmacokinetics; D051381:Rats; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists* / Q000378:metabolism; D012559:Schizophrenia / Q000188:drug therapy; D013329:Structure-Activity Relationship; D014018:Tissue Distribution
D001713:Biphenyl Compounds; D007189:Indans; D018094:Receptors, Metabotropic Glutamate; C108822:metabotropic glutamate receptor 2; D016244:Guanosine 5'-O-(3-Thiotriphosphate)