Potent Inhibition of Human phosphodiesterase-5 by Icariin Derivatives

J Nat Prod. 2008 Sep;71(9):1513-7. doi: 10.1021/np800049y. Epub 2008 Sep 9.

Abstract

Plant extracts traditionally used for male impotence (Tribulus terrestris, Ferula hermonis, Epimedium brevicornum, Cinnamomum cassia), and the individual compounds cinnamaldehyde, ferutinin, and icariin, were screened against phosphodiesterase-5A1 (PDE5A1) activity. Human recombinant PDE5A1 was used as the enzyme source. Only E. brevicornum extract (80% inhibition at 50 microg/mL) and its active principle icariin (1) (IC50 5.9 microM) were active. To improve its inhibitory activity, 1 was subjected to various structural modifications. Thus, 3,7-bis(2-hydroxyethyl)icaritin (5), where both sugars in 1 were replaced with hydroxyethyl residues, potently inhibited PDE5A1 with an IC50 very close to that of sildenafil (IC50 75 vs 74 nM). Thus, 5 was 80 times more potent than 1, and its selectivity versus phosphodiesterase-6 (PDE6) and cyclic adenosine monophosphate-phosphodiesterase (cAMP-PDE) was much higher in comparison with sildenafil. The improved pharmacodynamic profile and lack of cytotoxicity on human fibroblasts make compound 5 a promising candidate for further development.

MeSH terms

  • Cyclic Nucleotide Phosphodiesterases, Type 6 / antagonists & inhibitors
  • Epimedium / chemistry
  • Erectile Dysfunction / drug therapy
  • Ferula / chemistry
  • Flavonoids / chemistry
  • Flavonoids / pharmacology*
  • Humans
  • Inhibitory Concentration 50
  • Male
  • Molecular Structure
  • Phosphodiesterase 5 Inhibitors*
  • Phosphodiesterase Inhibitors / chemical synthesis*
  • Phosphodiesterase Inhibitors / chemistry
  • Phosphodiesterase Inhibitors / pharmacology*
  • Piperazines / pharmacology*
  • Plant Extracts / pharmacology
  • Purines / pharmacology
  • Sildenafil Citrate
  • Structure-Activity Relationship
  • Sulfones / pharmacology*
  • Tribulus / chemistry

Substances

  • Flavonoids
  • Phosphodiesterase 5 Inhibitors
  • Phosphodiesterase Inhibitors
  • Piperazines
  • Plant Extracts
  • Purines
  • Sulfones
  • 3,7-bis(2-hydroxyethyl)icaritin
  • Sildenafil Citrate
  • Cyclic Nucleotide Phosphodiesterases, Type 6
  • icariin