1,7- and 2,7-naphthyridine derivatives as potent and highly specific PDE5 inhibitors

Bioorg Med Chem Lett. 2003 Jul 21;13(14):2341-5. doi: 10.1016/s0960-894x(03)00440-2.

Abstract

Novel 1,7- and 2,7-naphthyridine derivatives, designed by the introduction of nitrogen atom into the phenyl ring of previously reported 4-aryl-1-isoquinolinone derivatives, were disclosed as a new structural class of potent and specific PDE5 inhibitors. Among them, 2,7-naphthyridine 4c showed potent PDE5 inhibition (IC(50)=0.23 nM) and one of the best PDE5 specificities against PDEs1-4,6 (>100,000-fold selective versus PDE1-4, 240-fold selective vs PDE6). This compound showed more potent relaxant effects on isolated rabbit corpus cavernosum (EC(30)=5.0 nM) than Sildenafil (EC(30)=8.7 nM). The compound 4c (T-0156) was selected for further biological and pharmacological evaluation of erectile dysfunction.

Publication types

  • Comparative Study

MeSH terms

  • 3',5'-Cyclic-GMP Phosphodiesterases
  • Animals
  • Cyclic Nucleotide Phosphodiesterases, Type 5
  • Genitalia, Male / drug effects
  • In Vitro Techniques
  • Indicators and Reagents
  • Isoenzymes / antagonists & inhibitors
  • Male
  • Muscle Relaxation / drug effects
  • Muscle, Smooth / drug effects
  • Naphthyridines / chemical synthesis*
  • Naphthyridines / pharmacology*
  • Phosphodiesterase Inhibitors / chemical synthesis*
  • Phosphodiesterase Inhibitors / pharmacology*
  • Phosphoric Diester Hydrolases / drug effects*
  • Piperazines / pharmacology
  • Purines
  • Rabbits
  • Sildenafil Citrate
  • Structure-Activity Relationship
  • Sulfones

Substances

  • Indicators and Reagents
  • Isoenzymes
  • Naphthyridines
  • Phosphodiesterase Inhibitors
  • Piperazines
  • Purines
  • Sulfones
  • Sildenafil Citrate
  • Phosphoric Diester Hydrolases
  • 3',5'-Cyclic-GMP Phosphodiesterases
  • Cyclic Nucleotide Phosphodiesterases, Type 5