A novel series of potent and selective PDE5 inhibitors with potential for high and dose-independent oral bioavailability

J Med Chem. 2006 Jun 15;49(12):3581-94. doi: 10.1021/jm060113e.


Sildenafil (5-[2-ethoxy-5-(4-methyl-1-piperazinylsulfonyl)phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one), a potent and selective phosphodiesterase type 5 (PDE5) inhibitor, provided the first oral treatment for male erectile dysfunction. The objective of the work reported in this paper was to combine high levels of PDE5 potency and selectivity with high and dose-independent oral bioavailability, to minimize the impact on the C(max) of any interactions with coadministered drugs in the clinic. This goal was achieved through identification of a lower clearance series with a high absorption profile, by replacing the 5'-piperazine sulfonamide in the sildenafil template with a 5'-methyl ketone. This novel series provided compounds with low metabolism in human hepatocytes, excellent caco-2 flux, and the potential for good aqueous solubility. The in vivo oral and iv pharmacokinetic profiles of example compounds confirmed the high oral bioavailability predicted from these in vitro screens. 5-(5-Acetyl-2-butoxy-3-pyridinyl)-3-ethyl-2-(1-ethyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (2) was selected for progression into the clinic.

MeSH terms

  • 3',5'-Cyclic-GMP Phosphodiesterases / antagonists & inhibitors*
  • 3',5'-Cyclic-GMP Phosphodiesterases / chemistry
  • Administration, Oral
  • Animals
  • Azetidines / chemical synthesis*
  • Azetidines / chemistry
  • Azetidines / pharmacology
  • Biological Availability
  • Caco-2 Cells
  • Crystallography, X-Ray
  • Cyclic Nucleotide Phosphodiesterases, Type 5
  • Dogs
  • Dose-Response Relationship, Drug
  • Erectile Dysfunction / drug therapy
  • Humans
  • Ketones / chemistry
  • Male
  • Models, Molecular
  • Molecular Structure
  • Pyrimidines / chemical synthesis*
  • Pyrimidines / chemistry
  • Pyrimidines / pharmacology
  • Pyrimidinones / chemical synthesis*
  • Pyrimidinones / chemistry
  • Pyrimidinones / pharmacology
  • Structure-Activity Relationship


  • 5-(5-acetyl-2-butoxy-3-pyridinyl)-3-ethyl-2-(1-ethyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one
  • Azetidines
  • Ketones
  • Pyrimidines
  • Pyrimidinones
  • 3',5'-Cyclic-GMP Phosphodiesterases
  • Cyclic Nucleotide Phosphodiesterases, Type 5
  • PDE5A protein, human