3-(2-Ethoxy-4-{4-[3-hydroxy-2-methyl-4-(3-methylbutanoyl)phenoxy]butoxy}phenyl)propanoic acid: a brain penetrant allosteric potentiator at the metabotropic glutamate receptor 2 (mGluR2).
We have identified and synthesized a brain penetrant propanoic acid as an allosteric potentiator of the metabotropic glutamate receptor 2. Structure-activity relationship studies directed toward improving the potency, level of potentiation and brain penetration led to the discovery of 8 (EC50=1200 nM, 77% potentiation, 119% brain/plasma in rat, 20 mpk i.p., brain level of 5700 nM).
Cube
Rowena V
RV
Department of Chemistry, Merck Research Laboratories, MRLSDB2, 3535 General Atomics Court, San Diego, CA 92121, USA. rowena_cube@merck.com
Vernier
Jean-Michel
JM
Hutchinson
John H
JH
Gardner
Michael F
MF
James
Joyce K
JK
Rowe
Blake A
BA
Schaffhauser
Herve
H
Daggett
Lorrie
L
Pinkerton
Anthony B
AB
D000494:Allosteric Regulation; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000502:physiology*; D002073:Butanes / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D007700:Kinetics; D008968:Molecular Conformation; D010647:Phenyl Ethers; D011422:Propionates / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D018094:Receptors, Metabotropic Glutamate / Q000187:drug effects / Q000502:physiology*; D013329:Structure-Activity Relationship
C504181:3-(2-ethoxy-4-(4-(3-hydroxy-2-methyl-4-(3-methylbutanoyl)phenoxy)butoxy)phenyl)propanoic acid; D002073:Butanes; D010647:Phenyl Ethers; D011422:Propionates; D018094:Receptors, Metabotropic Glutamate; C108822:metabotropic glutamate receptor 2; D016244:Guanosine 5'-O-(3-Thiotriphosphate)