Azetidine-based selective glycine transporter-1 (GlyT1) inhibitors with memory enhancing properties.
Atropisomerism
GlyT1
Glycine
Occupancy
Rotamers
Journal
Bioorganic & medicinal chemistry letters
ISSN: 1464-3405
Titre abrégé: Bioorg Med Chem Lett
Pays: England
ID NLM: 9107377
Informations de publication
Date de publication:
15 07 2020
15 07 2020
Historique:
received:
18
02
2020
revised:
22
04
2020
accepted:
23
04
2020
entrez:
13
6
2020
pubmed:
13
6
2020
medline:
2
6
2021
Statut:
ppublish
Résumé
A strategy to conformationally restrain a series of GlyT1 inhibitors identified potent analogs that exhibited slowly interconverting rotational isomers. Further studies to address this concern led to a series of azetidine-based inhibitors. Compound 26 was able to elevate CSF glycine levels in vivo and demonstrated potency comparable to Bitopertin in an in vivo rat receptor occupancy study. Compound 26 was subsequently shown to enhance memory in a Novel Object Recognition (NOR) behavioral study after a single dose of 0.03 mg/kg, and in a contextual fear conditioning (cFC) study after four QD doses of 0.01-0.03 mg/kg.
Identifiants
pubmed: 32527538
pii: S0960-894X(20)30314-0
doi: 10.1016/j.bmcl.2020.127214
pii:
doi:
Substances chimiques
Azetidines
0
Glycine Plasma Membrane Transport Proteins
0
SLC6A9 protein, human
0
azetidine
37S883XDWR
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
127214Informations de copyright
Copyright © 2020 Elsevier Ltd. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.