Scaffold hopping of fused piperidine-type NK3 receptor antagonists to reduce environmental impact

Bioorg Med Chem. 2019 May 15;27(10):2019-2026. doi: 10.1016/j.bmc.2019.03.059. Epub 2019 Apr 1.

Abstract

Neurokinin-3 receptor (NK3R) plays a pivotal role in the release of gonadotropin-releasing hormone in the hypothalamus-pituitary-gonadal (HPG) axis. To develop novel NK3R antagonists with less environmental toxicity, a series of heterocyclic scaffolds for the triazolopiperazine substructure in an NK3R antagonist fezolinetant were designed and synthesized. An isoxazolo[3,4-c]piperidine derivative exhibited moderate NK3R antagonistic activity and favorable properties that were decomposable under environmental conditions.

Keywords: Environmental impact; Fezolinetant; GnRH; NK3 receptor; Scaffold hopping.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Crystallography, X-Ray
  • Heterocyclic Compounds, 2-Ring / chemical synthesis
  • Heterocyclic Compounds, 2-Ring / chemistry
  • Inhibitory Concentration 50
  • Molecular Conformation
  • Photolysis
  • Piperidines / chemistry*
  • Piperidines / metabolism
  • Receptors, Neurokinin-3 / antagonists & inhibitors*
  • Receptors, Neurokinin-3 / metabolism
  • Structure-Activity Relationship
  • Sunlight
  • Thiadiazoles / chemical synthesis
  • Thiadiazoles / chemistry

Substances

  • Heterocyclic Compounds, 2-Ring
  • Piperidines
  • Receptors, Neurokinin-3
  • Thiadiazoles
  • fezolinetant