Substituted pyrazolopyridopyridazines as orally bioavailable potent and selective PDE5 inhibitors: potential agents for treatment of erectile dysfunction

J Med Chem. 2003 Feb 13;46(4):457-60. doi: 10.1021/jm0256068.

Abstract

Novel pyrazolopyridopyridazine derivatives have been prepared as potent and selective PDE5 inhibitors. Compound 6 has been identified as a more potent and selective PDE5 inhibitor than sildenafil (1). It is as efficacious as sildenafil in in vitro and in vivo PDE5 inhibition models, and it is orally bioavailable in rats and dogs. The superior isozyme selectivity of 6 is expected to exert less adverse effects in humans when used for erectile dysfunction treatment.

MeSH terms

  • 3',5'-Cyclic-GMP Phosphodiesterases / antagonists & inhibitors*
  • Administration, Oral
  • Animals
  • Biological Availability
  • Blood Pressure / drug effects
  • Cyclic Nucleotide Phosphodiesterases, Type 5
  • Dogs
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / pharmacokinetics
  • Enzyme Inhibitors / pharmacology
  • Erectile Dysfunction / drug therapy
  • Female
  • Male
  • Penis / blood supply
  • Pyridazines / chemical synthesis*
  • Pyridazines / pharmacokinetics
  • Pyridazines / pharmacology
  • Rabbits
  • Rats
  • Structure-Activity Relationship

Substances

  • Enzyme Inhibitors
  • Pyridazines
  • 3',5'-Cyclic-GMP Phosphodiesterases
  • Cyclic Nucleotide Phosphodiesterases, Type 5
  • Pde5a protein, rat