Discovery of GlyT1 inhibitors with improved pharmacokinetic properties.
Glycine transporter 1 (GlyT1) represents a novel target for the treatment of schizophrenia via the potentiation of glutamatergic NMDA receptors. The discovery of 4,4-disubstituted piperidine inhibitors of GlyT1 which exhibit improved pharmacokinetic properties, including oral bioavailability, is discussed.
Wolkenberg
Scott E
SE
Department of Medicinal Chemistry, Technology Enabled Synthesis Group, Merck & Co., Inc., PO Box 4, West Point, PA 19486, USA.
Zhao
Zhijian
Z
Wisnoski
David D
DD
Leister
William H
WH
O'Brien
Julie
J
Lemaire
Wei
W
Williams
David L
DL
Jacobson
Marlene A
MA
Sur
Cyrille
C
Kinney
Gene G
GG
Pettibone
Doug J
DJ
Tiller
Philip R
PR
Smith
Sheri
S
Gibson
Christopher
C
Ma
Bennett K
BK
Polsky-Fisher
Stacey L
SL
Lindsley
Craig W
CW
Hartman
George D
GD
D000818:Animals; D004285:Dogs; D055808:Drug Discovery / Q000379:methods*; D005998:Glycine / Q000096:biosynthesis; D050487:Glycine Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D051379:Mice; D008811:Mice, Inbred DBA; D016202:N-Methylaspartate / Q000737:chemistry / Q000494:pharmacology; D010880:Piperidines / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000493:pharmacokinetics*; D051381:Rats; D013379:Substrate Specificity; D013449:Sulfonamides / Q000138:chemical synthesis
D050487:Glycine Plasma Membrane Transport Proteins; D010880:Piperidines; D013449:Sulfonamides; D016202:N-Methylaspartate; D005998:Glycine