Fused bicyclic pyrrolizinones as new scaffolds for human NK1 antagonists

Bioorg Med Chem. 2008 Mar 1;16(5):2156-70. doi: 10.1016/j.bmc.2007.11.081. Epub 2007 Dec 5.

Abstract

Previous work on human NK(1) antagonists in which the core of the structure is a substituted pyrrolidine has been disclosed. These compounds showed good binding affinity and functional IP activity, however, many did not exhibit the necessary brain penetration for good in vivo activity. The discovery and preparation of a novel 5,5-fused pyrrolidine core is presented in this paper. This scaffold maintains the excellent binding affinity and functional IP activity of the previously reported compounds, but also exhibits excellent brain penetration as observed in a gerbil foot-tapping assay. The determination of the core structural stereochemistry, which eventually led to the final synthesis of a single active diastereomer, is described.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amides / chemistry
  • Bridged Bicyclo Compounds, Heterocyclic / chemical synthesis*
  • Bridged Bicyclo Compounds, Heterocyclic / chemistry
  • Bridged Bicyclo Compounds, Heterocyclic / pharmacology*
  • Epoxy Compounds / chemistry
  • Humans
  • Hydroxylation
  • Methylation
  • Molecular Structure
  • Neurokinin-1 Receptor Antagonists*
  • Pyrroles / chemical synthesis*
  • Pyrroles / chemistry
  • Pyrroles / pharmacology*
  • Receptors, Neurokinin-1 / metabolism*
  • Stereoisomerism
  • Urea / chemistry

Substances

  • Amides
  • Bridged Bicyclo Compounds, Heterocyclic
  • Epoxy Compounds
  • Neurokinin-1 Receptor Antagonists
  • Pyrroles
  • Receptors, Neurokinin-1
  • Urea