Prodrugs of perzinfotel with improved oral bioavailability

J Med Chem. 2009 Feb 12;52(3):771-8. doi: 10.1021/jm8011799.


Previous studies with perzinfotel (1), a potent, selective, competitive NMDA receptor antagonist, showed it to be efficacious in inflammatory and neuropathic pain models. To increase the low oral bioavailability of 1 (3-5%), prodrug derivatives (3a-h) were synthesized and evaluated. The oxymethylene-spaced diphenyl analogue 3a demonstrated good stability at acidic and neutral pH, as well as in simulated gastric fluid. In rat plasma, 3a was rapidly converted to 1 via 2a. Pharmacokinetic studies indicated that the amount of systemic exposure of 1 produced by a 10 mg/kg oral dose of 3a was 2.5-fold greater than that produced by a 30 mg/kg oral dose of 1. Consistent with these results, 3a was significantly more potent and had a longer duration of activity than 1 following oral administration in a rodent model of inflammatory pain. Taken together, these results demonstrate that an oxymethylene-spaced prodrug approach increased the bioavailability of 1.

MeSH terms

  • Administration, Oral
  • Animals
  • Azabicyclo Compounds / administration & dosage
  • Azabicyclo Compounds / pharmacokinetics*
  • Bile / metabolism
  • Biological Availability
  • Diphosphonates / chemical synthesis
  • Diphosphonates / pharmacokinetics
  • Drug Stability
  • Gastric Juice / metabolism
  • Male
  • Organophosphonates / administration & dosage
  • Organophosphonates / pharmacokinetics*
  • Prodrugs / pharmacokinetics*
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, N-Methyl-D-Aspartate / antagonists & inhibitors


  • Azabicyclo Compounds
  • Diphosphonates
  • Organophosphonates
  • Prodrugs
  • Receptors, N-Methyl-D-Aspartate
  • EAA-090