Synthesis of quinoline derivatives: discovery of a potent and selective phosphodiesterase 5 inhibitor for the treatment of Alzheimer's disease

Eur J Med Chem. 2013 Feb:60:285-94. doi: 10.1016/j.ejmech.2012.12.009. Epub 2012 Dec 14.

Abstract

Phosphodiesterase type 5 (PDE5) mediates the degradation of cGMP in a variety of tissues including brain. Recent studies have demonstrated the importance of the nitric oxide/cGMP/cAMP-responsive element-binding protein (CREB) pathway to the process of learning and memory. Thus, PDE5 inhibitors (PDE5Is) are thought to be promising new therapeutic agents for the treatment of Alzheimer's disease (AD), a neurodegenerative disorder characterized by memory loss. To explore this possibility, a series of quinoline derivatives were synthesized and evaluated. We found that compound 7a selectively inhibits PDE5 with an IC(50) of 0.27 nM and readily crosses the blood brain barrier. In an in vivo mouse model of AD, compound 7a rescues synaptic and memory defects. Quinoline-based, CNS-permeant PDE5Is have potential for AD therapeutic development.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / drug therapy*
  • Animals
  • Disease Models, Animal
  • Drug Discovery*
  • Female
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Molecular Structure
  • Phosphodiesterase 5 Inhibitors / chemical synthesis
  • Phosphodiesterase 5 Inhibitors / chemistry
  • Phosphodiesterase 5 Inhibitors / therapeutic use*
  • Quinolines / chemical synthesis
  • Quinolines / chemistry
  • Quinolines / therapeutic use*

Substances

  • Phosphodiesterase 5 Inhibitors
  • Quinolines
  • quinoline