title: An octahydro-cyclopenta[c]pyrrole series of inhibitors of the type 1 glycine transporter.
abstract: 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.
authors.affiliation: Pfizer Global Research & Development, Eastern Point Road, Groton CT 06340, United States.
authors.forename: John A
authors.initials: JA
authors.lastname: Lowe
authors.forename: Shari L
authors.initials: SL
authors.lastname: Deninno
authors.forename: Susan E
authors.initials: SE
authors.lastname: Drozda
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Schmidt
authors.forename: Karen M
authors.initials: KM
authors.lastname: Ward
authors.forename: F
authors.initials: F
authors.lastname: David Tingley
authors.forename: Mark
authors.initials: M
authors.lastname: Sanner
authors.forename: Don
authors.initials: D
authors.lastname: Tunucci
authors.forename: James
authors.initials: J
authors.lastname: Valentine
mesh_terms: 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
chemical_list: D003517:Cyclopentanes; D050487:Glycine Plasma Membrane Transport Proteins; D011758:Pyrroles; C493268:SLC6A9 protein, human