title: Inhibitors of the glycine transporter type-2 (GlyT-2): synthesis and biological activity of benzoylpiperidine derivatives.
abstract: A series of benzoylpiperidine analogs related to 4a was prepared, and their ability to inhibit the uptake of [(14)C]-glycine in COS7 cells transfected with human glycine transporter type-2 (GlyT-2) was evaluated. Small structural changes to the benzoylpiperidine region of the molecule led to a significant decrease in GlyT-2 inhibitory activity. In contrast, the distal aryl ring was more tolerant to functional group modifications and could accommodate a variety of substitutes at the C-2 or C-3 positions. Comparable activities to 4a were obtained by replacing the anilino nitrogen with an ether linkage 27 or by exchanging the isopropoxy ether moiety with an isopropyl amino group 15. A distinct preference for a 2-carbon tether (n=1) was observed relative to the corresponding 3-carbon homolog (n=2).
authors.affiliation: Johnson & Johnson Pharmaceutical Research and Development, LLC, 3210 Merryfield Row, San Diego, CA 92121, USA. rwolin@prdus.jnj.com
authors.forename: Ronald L
authors.initials: RL
authors.lastname: Wolin
authors.forename: Alejandro
authors.initials: A
authors.lastname: Santillán
authors.forename: Liu
authors.initials: L
authors.lastname: Tang
authors.forename: Charles
authors.initials: C
authors.lastname: Huang
authors.forename: Xiaoxia
authors.initials: X
authors.lastname: Jiang
authors.forename: Timothy W
authors.initials: TW
authors.lastname: Lovenberg
mesh_terms: D026921:Amino Acid Transport Systems, Neutral / Q000037:antagonists & inhibitors* / Q000235:genetics; D000818:Animals; D001565:Benzoates / Q000737:chemistry*; D001692:Biological Transport / Q000187:drug effects; D019556:COS Cells; D002522:Chlorocebus aethiops; D005998:Glycine / Q000378:metabolism; D050487:Glycine Plasma Membrane Transport Proteins; D014179:Neurotransmitter Uptake Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D026921:Amino Acid Transport Systems, Neutral; D001565:Benzoates; D050487:Glycine Plasma Membrane Transport Proteins; D014179:Neurotransmitter Uptake Inhibitors; D010880:Piperidines; D005998:Glycine