Novel GlyT1 inhibitor chemotypes by scaffold hopping. Part 1: development of a potent and CNS penetrant [3.1.0]-based lead

Bioorg Med Chem Lett. 2014 Feb 15;24(4):1067-70. doi: 10.1016/j.bmcl.2014.01.013. Epub 2014 Jan 13.

Abstract

This Letter describes the development and SAR of a novel series of GlyT1 inhibitors derived from a scaffold hopping approach that provided a robust intellectual property position, in lieu of a traditional, expensive HTS campaign. Members within this new [3.1.0]-based series displayed excellent GlyT1 potency, selectivity, free fraction, CNS penetration and efficacy in a preclinical model of schizophrenia (prepulse inhibition).

Keywords: GlyT1; Scaffold hopping; Schizophrenia; Transporter.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Bridged Bicyclo Compounds / chemical synthesis
  • Bridged Bicyclo Compounds / chemistry
  • Bridged Bicyclo Compounds / pharmacology*
  • Dose-Response Relationship, Drug
  • Glycine Plasma Membrane Transport Proteins / antagonists & inhibitors*
  • Humans
  • Molecular Structure
  • Piperidines / chemical synthesis
  • Piperidines / chemistry
  • Piperidines / pharmacology*
  • Structure-Activity Relationship

Substances

  • Bridged Bicyclo Compounds
  • Glycine Plasma Membrane Transport Proteins
  • Piperidines
  • SLC6A9 protein, human
  • piperidine