Allosteric potentiators of the metabotropic glutamate receptor 2 (mGlu2). Part 2: 4-thiopyridyl acetophenones as non-tetrazole containing mGlu2 receptor potentiators.
We have identified and synthesized a series of 4-thiopyridyl acetophenones as positive allosteric potentiators of the metabotropic glutamate receptor 2. Structure-activity relationship studies directed toward replacement of the tetrazole in the initial lead led to the discovery of 16 (EC(50)=340 nM), which showed improved brain penetration over the initial lead.
Pinkerton
Anthony B
AB
Merck Research Laboratories, MRLSDB2, 3535 General Atomics Court, San Diego, CA 92121, USA. anthony_pinkerton@merck.com
Cube
Rowena V
RV
Hutchinson
John H
JH
James
Joyce K
JK
Gardner
Michael F
MF
Schaffhauser
Hervé
H
Rowe
Blake A
BA
Daggett
Lorrie P
LP
Vernier
Jean-Michel
JM
D000098:Acetophenones / Q000737:chemistry / Q000378:metabolism*; D000494:Allosteric Regulation / Q000502:physiology; D000818:Animals; D001921:Brain / Q000378:metabolism; D002460:Cell Line; D006801:Humans; D011485:Protein Binding / Q000502:physiology; D011725:Pyridines / Q000737:chemistry* / Q000378:metabolism*; D051381:Rats; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013777:Tetrazoles
D000098:Acetophenones; D011725:Pyridines; D018094:Receptors, Metabotropic Glutamate; D013777:Tetrazoles; C108822:metabotropic glutamate receptor 2