Optimization of the Aminopyridopyrazinones Class of PDE5 Inhibitors: Discovery of 3-[(trans-4-hydroxycyclohexyl)amino]-7-(6-methoxypyridin-3-yl)-1-(2-propoxyethyl)pyrido[3,4-b]pyrazin-2(1H)-one

Bioorg Med Chem Lett. 2009 Sep 1;19(17):5209-13. doi: 10.1016/j.bmcl.2009.07.019. Epub 2009 Jul 10.

Abstract

We describe efforts to improve the pharmacokinetic profile of the aminopyridopyrazinone class of PDE5 inhibitors. These efforts led to the discovery of 3-[(trans-4-hydroxycyclohexyl)amino]-7-(6-methoxypyridin-3-yl)-1-(2-propoxyethyl)pyrido[3,4-b]pyrazin-2(1H)-one, a potent and selective inhibitor of PDE5 with an excellent PK profile.

MeSH terms

  • Animals
  • Cyclic Nucleotide Phosphodiesterases, Type 5 / metabolism
  • Cyclic Nucleotide Phosphodiesterases, Type 6 / antagonists & inhibitors
  • Cyclic Nucleotide Phosphodiesterases, Type 6 / metabolism
  • Dogs
  • Drug Discovery
  • Humans
  • Phosphodiesterase 5 Inhibitors*
  • Phosphodiesterase Inhibitors / chemical synthesis
  • Phosphodiesterase Inhibitors / chemistry*
  • Phosphodiesterase Inhibitors / pharmacokinetics
  • Protein Isoforms / antagonists & inhibitors
  • Protein Isoforms / metabolism
  • Pyrazines / chemical synthesis
  • Pyrazines / chemistry*
  • Pyrazines / pharmacokinetics
  • Pyridines / chemical synthesis
  • Pyridines / chemistry*
  • Pyridines / pharmacokinetics
  • Rats
  • Rats, Inbred SHR
  • Structure-Activity Relationship

Substances

  • Phosphodiesterase 5 Inhibitors
  • Phosphodiesterase Inhibitors
  • Protein Isoforms
  • Pyrazines
  • Pyridines
  • Cyclic Nucleotide Phosphodiesterases, Type 5
  • Cyclic Nucleotide Phosphodiesterases, Type 6