A novel series of positive modulators of the AMPA receptor: structure-based lead optimization.
Starting from lead compound 1, we demonstrate how X-ray structural data can be used to understand SAR and expediently optimize bioavailability in a novel series of AMPA receptor modulators, furnishing 5 with improved bioavailability and robust in vivo activity.
Jamieson
Craig
C
Merck Research Laboratories, MSD, Newhouse, Motherwell, Lanarkshire, UK. craig.jamieson@strath.ac.uk
Campbell
Robert A
RA
Cumming
Iain A
IA
Gillen
Kevin J
KJ
Gillespie
Jonathan
J
Kazemier
Bert
B
Kiczun
Michael
M
Lamont
Yvonne
Y
Lyons
Amanda J
AJ
Maclean
John K F
JK
Martin
Frederic
F
Moir
Elizabeth M
EM
Morrow
John A
JA
Pantling
John
J
Rankovic
Zoran
Z
Smith
Lynn
L
D000494:Allosteric Regulation; D000588:Amines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D001682:Biological Availability; D018360:Crystallography, X-Ray; D015195:Drug Design; D006801:Humans; D008958:Models, Molecular; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D018091:Receptors, AMPA / Q000737:chemistry / Q000378:metabolism*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000588:Amines; D011720:Pyrazoles; D018091:Receptors, AMPA