Gastric-sparing nitric oxide-releasable 'true' prodrugs of aspirin and naproxen

Bioorg Med Chem Lett. 2014 Dec 15;24(24):5587-5592. doi: 10.1016/j.bmcl.2014.10.096. Epub 2014 Nov 5.

Abstract

Nitric oxide-releasing non-steroidal anti-inflammatory drugs (NO-NSAIDs) are gaining attention as potentially gastric-sparing NSAIDs. Herein, we report a novel class of '1-(nitrooxy)ethyl ester' group-containing NSAIDS as efficient NO releasing 'true' prodrugs of aspirin and naproxen. While an aspirin prodrug exhibited comparable oral bioavailability and antiplatelet activity (i.e., TXB2 inhibition) to those of aspirin, a naproxen prodrug exhibited better bioavailability than naproxen. These promising NO-NSAIDs protected experimental rats from gastric damage. We therefore believe that these promising NO-NSAIDs could represent a new class of potentially 'Safe NSAIDs' for the treatment of arthritic pain, inflammation and cardiovascular disorders in the case of NO-aspirin.

Keywords: Gastric-sparing NSAIDs; NO-NSAIDs; NO-aspirin; NO-naproxen; Nitric oxide donors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal / chemistry
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacokinetics
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology
  • Anti-Inflammatory Agents, Non-Steroidal / toxicity
  • Area Under Curve
  • Aspirin / analogs & derivatives*
  • Aspirin / chemistry
  • Aspirin / pharmacokinetics
  • Aspirin / pharmacology
  • Aspirin / toxicity
  • Blood Platelets / drug effects
  • Blood Platelets / enzymology
  • Cyclooxygenase 1 / chemistry
  • Cyclooxygenase 1 / metabolism
  • Cyclooxygenase 2 / chemistry
  • Cyclooxygenase 2 / metabolism
  • Drug Design
  • Drug Stability
  • Gastric Mucosa / drug effects
  • Half-Life
  • Humans
  • Naproxen / analogs & derivatives*
  • Naproxen / chemistry
  • Naproxen / pharmacokinetics
  • Naproxen / pharmacology
  • Naproxen / toxicity
  • Nitrates / chemistry*
  • Nitrates / pharmacokinetics
  • Nitrates / pharmacology
  • Nitrates / toxicity
  • Nitric Oxide / metabolism
  • Platelet Aggregation Inhibitors / chemistry
  • Platelet Aggregation Inhibitors / pharmacokinetics
  • Platelet Aggregation Inhibitors / pharmacology
  • Platelet Aggregation Inhibitors / toxicity
  • Prodrugs / chemistry*
  • Prodrugs / pharmacokinetics
  • Prodrugs / pharmacology
  • Prodrugs / toxicity
  • ROC Curve
  • Rats
  • Rats, Sprague-Dawley
  • Thromboxane B2 / metabolism

Substances

  • Anti-Inflammatory Agents, Non-Steroidal
  • N-acetyl-S-(alpha-methyl-4-(2-methylpropyl)benzeneacetyl)cysteine 4-(nitrooxy)butyl ester
  • Nitrates
  • Platelet Aggregation Inhibitors
  • Prodrugs
  • naproxen-n-butyl nitrate
  • Nitric Oxide
  • Thromboxane B2
  • Naproxen
  • Cyclooxygenase 1
  • Cyclooxygenase 2
  • Aspirin