Dihydropyridine neuropeptide Y Y1 receptor antagonists 2. bioisosteric urea replacements

Bioorg Med Chem. 2004 Jan 15;12(2):507-21. doi: 10.1016/j.bmc.2003.10.016.

Abstract

Structure-activity studies around the urea linkage in BMS-193885 (4a) identified the cyanoguanidine moiety as an effective urea replacement in a series of dihydropyridine NPY Y(1) receptor antagonists. In comparison to urea 4a (K(i)=3.3 nM), cyanoguanidine 20 (BMS-205749) displayed similar binding potency at the Y(1) receptor (K(i)=5.1 nM) and full functional antagonism (K(b)=2.6 nM) in SK-N-MC cells. Cyanoguanidine 20 also demonstrated improved permeability properties in Caco-2 cells in comparison to urea 4a (43 vs 19 nm/s).

MeSH terms

  • Caco-2 Cells
  • Cell Membrane Permeability / drug effects
  • Cells, Cultured
  • Dihydropyridines / chemistry
  • Dihydropyridines / pharmacology
  • Drug Evaluation, Preclinical / methods
  • Guanidines / chemistry
  • Humans
  • Phenylurea Compounds / chemistry
  • Phenylurea Compounds / pharmacology
  • Receptors, Neuropeptide Y / antagonists & inhibitors*
  • Receptors, Neuropeptide Y / metabolism
  • Stereoisomerism
  • Structure-Activity Relationship
  • Urea / chemistry*

Substances

  • BMS 193885
  • Dihydropyridines
  • Guanidines
  • Phenylurea Compounds
  • Receptors, Neuropeptide Y
  • neuropeptide Y-Y1 receptor
  • 1,4-dihydropyridine
  • Urea
  • dicyandiamido