Design, synthesis, and biological evaluation of 3-[4-(2-hydroxyethyl)piperazin-1-yl]-7-(6-methoxypyridin-3-yl)-1-(2-propoxyethyl)pyrido[3,4-b]pyrazin-2(1H)-one, a potent, orally active, brain penetrant inhibitor of phosphodiesterase 5 (PDE5)

J Med Chem. 2010 Mar 25;53(6):2656-60. doi: 10.1021/jm901781q.

Abstract

We recently described a novel series of aminopyridopyrazinones as PDE5 inhibitors. Efforts toward optimization of this series culminated in the identification of 3-[4-(2-hydroxyethyl)piperazin-1-yl]-7-(6-methoxypyridin-3-yl)-1-(2-propoxyethyl)pyrido[3,4-b]pyrazin-2(1H)-one, which possessed an excellent potency and selectivity profile and demonstrated robust in vivo blood pressure lowering in a spontaneously hypertensive rat (SHR) model. Furthermore, this compound is brain penetrant and will be a useful agent for evaluating the therapeutic potential of central inhibition of PDE5. This compound has recently entered clinical trials.

MeSH terms

  • Administration, Oral
  • Animals
  • Biological Availability
  • Blood Pressure / drug effects
  • Brain / metabolism*
  • Cyclic Nucleotide Phosphodiesterases, Type 5 / metabolism
  • Dose-Response Relationship, Drug
  • Drug Design
  • Humans
  • Male
  • Models, Chemical
  • Molecular Structure
  • Phosphodiesterase 5 Inhibitors*
  • Phosphodiesterase Inhibitors / chemical synthesis*
  • Phosphodiesterase Inhibitors / pharmacokinetics
  • Phosphodiesterase Inhibitors / pharmacology*
  • Pyrazines / chemical synthesis*
  • Pyrazines / pharmacokinetics
  • Pyrazines / pharmacology*
  • Pyridines / chemical synthesis*
  • Pyridines / pharmacokinetics
  • Pyridines / pharmacology*
  • Rats
  • Rats, Inbred SHR
  • Rats, Sprague-Dawley

Substances

  • 3-(4-(2-hydroxyethyl)piperazin-1-yl)-7-(6-methoxypyridin-3-yl)-1-(2-propoxyethyl)pyrido(3,4-b)pyrazin-2(1H)-one
  • Phosphodiesterase 5 Inhibitors
  • Phosphodiesterase Inhibitors
  • Pyrazines
  • Pyridines
  • Cyclic Nucleotide Phosphodiesterases, Type 5