Azetidine-based selective glycine transporter-1 (GlyT1) inhibitors with memory enhancing properties

Bioorg Med Chem Lett. 2020 Jul 15;30(14):127214. doi: 10.1016/j.bmcl.2020.127214. Epub 2020 Apr 25.

Abstract

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.

Keywords: Atropisomerism; GlyT1; Glycine; Occupancy; Rotamers.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Azetidines / chemical synthesis
  • Azetidines / chemistry
  • Azetidines / pharmacology*
  • Dose-Response Relationship, Drug
  • Glycine Plasma Membrane Transport Proteins / antagonists & inhibitors*
  • HEK293 Cells
  • Humans
  • Memory / drug effects*
  • Molecular Structure
  • Structure-Activity Relationship

Substances

  • Azetidines
  • Glycine Plasma Membrane Transport Proteins
  • SLC6A9 protein, human
  • azetidine