Novel GlyT1 inhibitor chemotypes by scaffold hopping. Part 2: development of a [3.3.0]-based series and other piperidine bioisosteres

Bioorg Med Chem Lett. 2014 Feb 15;24(4):1062-6. doi: 10.1016/j.bmcl.2014.01.011. 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, in lieu of an HTS campaign, which provided intellectual property position. Members within this new [3.3.0]-based series displayed excellent GlyT1 potency, selectivity, free fraction, and modest CNS penetration. Moreover, enantioselective GlyT1 inhibition was observed, within this novel series and a number of other piperidine bioisosteric cores.

Keywords: GlyT1; Scaffold hopping; Schizophrenia; Transporter.

Publication types

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

MeSH terms

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

Substances

  • Glycine Plasma Membrane Transport Proteins
  • Piperidines
  • SLC6A9 protein, human
  • Sulfonamides
  • piperidine