An octahydro-cyclopenta[c]pyrrole series of inhibitors of the type 1 glycine transporter.
We describe a novel series of inhibitors of the type 1 glycine transporter (GlyT1) as an approach to relieving the glutamatergic deficit that is thought to underlie schizophrenia. Synthesis and SAR follow-up of a series of octahydro-cyclopenta[c]pyrrole derivatives afforded potent in vitro inhibition of GlyT1 as well as in vivo activity in elevating CSF glycine. We also found that a 3-O(c-pentyl), 4-F substituent may serve as a surrogate for the widely used 3-trifluoromethoxy group, suggesting its application as an isostere for future medicinal chemistry studies.
Lowe
John A
JA
Pfizer Global Research & Development, Eastern Point Road, Groton CT 06340, United States.
Deninno
Shari L
SL
Drozda
Susan E
SE
Schmidt
Christopher J
CJ
Ward
Karen M
KM
David Tingley
F
F
Sanner
Mark
M
Tunucci
Don
D
Valentine
James
J
D000818:Animals; D002460:Cell Line; D003517:Cyclopentanes / Q000737:chemistry* / Q000494:pharmacology; D004285:Dogs; D050487:Glycine Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology; D006801:Humans; D008861:Microsomes / Q000187:drug effects / Q000502:physiology; D011758:Pyrroles / Q000737:chemistry* / Q000494:pharmacology
D003517:Cyclopentanes; D050487:Glycine Plasma Membrane Transport Proteins; D011758:Pyrroles; C493268:SLC6A9 protein, human