Design, synthesis and evaluation of constrained tetrahydroimidazopyrimidine derivatives as antagonists of corticotropin-releasing factor type 1 receptor (CRF1R)

Bioorg Med Chem Lett. 2010 Mar 15;20(6):1905-9. doi: 10.1016/j.bmcl.2010.01.127. Epub 2010 Feb 4.

Abstract

Several tetrahydroimidazopyrimidines were prepared using silver assisted cyclization as the key step. The binding affinities of compounds thus prepared were evaluated in vitro toward hCRF(1)R. Initial lead compound 16 (K(i)=32 nM) demonstrated modest putative anxiolytic effects in the mouse canopy test. Further optimization using parallel synthesis provided compounds with K(i)'s <50 nM.

MeSH terms

  • Animals
  • CRF Receptor, Type 1
  • Cyclization
  • Drug Design*
  • Mice
  • Pyrimidines / chemical synthesis*
  • Pyrimidines / chemistry
  • Pyrimidines / pharmacology*
  • Receptors, Corticotropin-Releasing Hormone / antagonists & inhibitors*

Substances

  • Pyrimidines
  • Receptors, Corticotropin-Releasing Hormone
  • CRF Receptor, Type 1