Novel 4-(4-aryl)cyclohexyl-1-(2-pyridyl)piperazines as Delta(8)-Delta(7) sterol isomerase (emopamil binding protein) selective ligands with antiproliferative activity

J Med Chem. 2008 Dec 11;51(23):7523-31. doi: 10.1021/jm800965b.

Abstract

To find Delta(8)-Delta(7) sterol isomerase (EBP) selective ligands, various arylpiperazines previously studied and structurally related to some sigma receptors ligands were preliminarily screened. Consequently, a novel series of 2- or 2,6-disubstituted (CH(3), CH(3)O, Cl, F) cis- and trans-4-(4-aryl)cyclohexyl-1-(2-pyridyl)piperazines was developed. Radioreceptor binding assays evidenced cis-19, cis-30 and cis-33 as new ligands with nanomolar affinity toward EBP site and a good selectivity relative to EBP-related sigma receptors. The most selective 2,6-dimethoxy derivative (cis-33) demonstrated the highest potency (EC(50) = 12.9 microM) and efficacy (70%) in inhibiting proliferation of human prostate cancer PC-3 cell line. Among the reference compounds, sigma(2) agonist 36 (PB28) reached the maximum efficacy (100%), suggesting the contribution of the sigma(2) receptor to the antiproliferative activity. This novel class of EBP inhibitors represents a valuable tool for investigating the last steps of cholesterol biosynthesis and related pathologies, as well as a starting point for developing new anticancer drugs.

MeSH terms

  • Apoptosis / drug effects
  • Binding Sites / drug effects
  • Cell Proliferation / drug effects
  • Crystallography, X-Ray
  • Dose-Response Relationship, Drug
  • Drug Design
  • Drug Screening Assays, Antitumor
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Ligands
  • Models, Molecular
  • Molecular Structure
  • Piperazines / chemical synthesis
  • Piperazines / chemistry
  • Piperazines / pharmacology*
  • Pyridines / chemical synthesis
  • Pyridines / chemistry
  • Pyridines / pharmacology*
  • Stereoisomerism
  • Steroid Isomerases / antagonists & inhibitors*
  • Structure-Activity Relationship
  • Tumor Cells, Cultured

Substances

  • Enzyme Inhibitors
  • Ligands
  • Piperazines
  • Pyridines
  • Steroid Isomerases
  • delta(8)-delta(7)-sterol isomerase