Pyrroloquinolone PDE5 inhibitors with improved pharmaceutical profiles for clinical studies on erectile dysfunction

J Med Chem. 2005 Mar 24;48(6):2126-33. doi: 10.1021/jm0401098.


We previously reported a series of potent and selective pyrimidinyl pyrroloquinolone PDE5 inhibitors such as 2a for potential use in male erectile dysfunction (MED) (Sui, Z.; Guan, J.; Macielag, M. J.; Jiang, W.; Zhang, S.; Qiu, Y.; Kraft, P., Bhattacharjee, S.; John, T. M.; Craig, E.; Haynes-Johnson, D.; Clancy, J. J. Med. Chem. 2002, 45, 4094-4096). Unfortunately, the low aqueous solubility and poor oral bioavailability rendered them undesirable development candidates. To address this issue, we designed a series of analogues using two approaches: increasing the overall basicity and reducing molecular weight of the lead. Through earlier SAR studies, we discovered that the PDE5 potency of the pyrroloquinolones is insensitive to substitution on the pyrrole nitrogen. Basic functional groups such as pyridines and benzimidazoles were appended via the aromatic ring connected to the pyrrole nitrogen. Several truncated analogues were also designed and synthesized to improve oral absorption. These modifications allowed us to identify analogues with good oral bioavailability in rats, dogs, and monkeys while the high potency against PDE5 and desirable selectivity versus other PDE isozymes were maintained. Compounds R-11e and R-11l were selected as development candidates for MED and other indications.

MeSH terms

  • 3',5'-Cyclic-GMP Phosphodiesterases / antagonists & inhibitors*
  • Animals
  • Biological Availability
  • Blood Pressure / drug effects
  • Cell Line
  • Cyclic GMP / biosynthesis
  • Cyclic Nucleotide Phosphodiesterases, Type 5
  • Dogs
  • Electric Stimulation
  • Erectile Dysfunction / drug therapy
  • Macaca mulatta
  • Male
  • Penis / blood supply
  • Penis / drug effects
  • Pyrroles / chemical synthesis*
  • Pyrroles / pharmacokinetics
  • Pyrroles / pharmacology
  • Quinolones / chemical synthesis*
  • Quinolones / pharmacokinetics
  • Quinolones / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Solubility
  • Stereoisomerism
  • Structure-Activity Relationship


  • 1,2,3,4-tetrahydro-2-(5-(2-pyridinyl)pyrimidin-2-yl)-3-(3,4-dihydrobenzofuranyl)-9H-pyrrolo(3,4-b)quinolin-9-one
  • 3-(2,3-dihydrobenzofuran-5-yl)-2-pyridin-2-yl-1,2,3,4-tetrahydropyrrolo(3,4-b)quinolin-9-one
  • Pyrroles
  • Quinolones
  • 3',5'-Cyclic-GMP Phosphodiesterases
  • Cyclic Nucleotide Phosphodiesterases, Type 5
  • Pde5a protein, rat
  • Cyclic GMP