The discovery of a structurally novel class of inhibitors of the type 1 glycine transporter.
The type 1 glycine transporter plays an important in regulating homeostatic glycine levels in the brain that are relevant to the activation of the NMDA receptor by the excitatory neurotransmitter glutamate. We describe herein the structure-activity relationships (SAR) of a structurally novel class of GlyT1 inhibitors following on a lead derived from high throughput screening, which shows good selectivity for GlyT1 and potent activity in elevating CSF levels of glycine.
Lowe
John A
JA
Pfizer Global Research and Development, Groton, CT 06340, United States. jal3rd@gmail.com
Hou
Xinjun
X
Schmidt
Christopher
C
David Tingley
F
F
McHardy
Stan
S
Kalman
Monica
M
Deninno
Shari
S
Sanner
Mark
M
Ward
Karen
K
Lebel
Lorraine
L
Tunucci
Don
D
Valentine
James
J
Bronk
Brian S
BS
Schaeffer
Eric
E
D001372:Aza Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D002460:Cell Line; D015195:Drug Design; D005998:Glycine / Q000378:metabolism; D050487:Glycine Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006574:Heterocyclic Compounds, 2-Ring / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D013329:Structure-Activity Relationship
D001372:Aza Compounds; D050487:Glycine Plasma Membrane Transport Proteins; D006574:Heterocyclic Compounds, 2-Ring; D016194:Receptors, N-Methyl-D-Aspartate; D005998:Glycine