Identification of a novel spiropiperidine opioid receptor-like 1 antagonist class by a focused library approach featuring 3D-pharmacophore similarity

J Med Chem. 2006 Feb 9;49(3):847-9. doi: 10.1021/jm0509851.

Abstract

A focused library approach identifying novel leads to develop a potent ORL1 antagonist is described. Beginning from a compound identified by random screening, an exploratory library that exhibited a diverse display of pharmacophores was designed. After evaluating ORL1 antagonistic activity, a highly focused library was designed based on 3D-pharmacophore similarity to known actives. A novel D-proline amide class was identified in this library and was found to possess potent ORL1 antagonistic activity.

MeSH terms

  • Animals
  • Binding, Competitive
  • CHO Cells
  • Combinatorial Chemistry Techniques
  • Cricetinae
  • Cricetulus
  • Humans
  • Hydrophobic and Hydrophilic Interactions
  • Models, Molecular
  • Molecular Structure
  • Narcotic Antagonists*
  • Piperidines / chemical synthesis*
  • Piperidines / chemistry
  • Proline / analogs & derivatives
  • Proline / chemical synthesis
  • Proline / chemistry
  • Proline / pharmacology
  • Quantitative Structure-Activity Relationship
  • Radioligand Assay
  • Receptors, Opioid / agonists
  • Receptors, Opioid / chemistry*
  • Spiro Compounds / chemical synthesis*
  • Spiro Compounds / chemistry
  • Spiro Compounds / pharmacology
  • Stereoisomerism

Substances

  • Narcotic Antagonists
  • Piperidines
  • Receptors, Opioid
  • Spiro Compounds
  • Proline
  • nociceptin receptor
  • prolinamide