A novel series of positive modulators of the AMPA receptor: discovery and structure based hit-to-lead studies.
Starting from an HTS derived hit 1, application of biostructural data facilitated rapid optimization to lead 22, a novel AMPA receptor modulator. This is the first demonstration of how structure based drug design can be exploited in an optimization program for a glutamate receptor.
Jamieson
Craig
C
Merck Research Laboratories, MSD, Motherwell, Lanarkshire ML1 5SH, UK.
Basten
Stephanie
S
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
Moir
Elizabeth M
EM
Morrow
John A
JA
Papakosta
Marianthi
M
Rankovic
Zoran
Z
Smith
Lynn
L
D000494:Allosteric Regulation; D000818:Animals; D001665:Binding Sites; D018360:Crystallography, X-Ray; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D057166:High-Throughput Screening Assays; D006801:Humans; D007191:Indazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D008861:Microsomes / Q000378:metabolism; D017434:Protein Structure, Tertiary; D051381:Rats; D018091:Receptors, AMPA / Q000737:chemistry* / Q000378:metabolism; D013876:Thiophenes / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology
D007191:Indazoles; D018091:Receptors, AMPA; D013876:Thiophenes