Novel nonsteroidal anti-inflammatory drug derivatives with markedly reduced ulcerogenic properties in the rat

Gastroenterology. 1994 Jul;107(1):173-9. doi: 10.1016/0016-5085(94)90074-4.


Background/aims: The use of nonsteroidal anti-inflammatory drugs (NSAIDs) is limited by their ability to induce gastrointestinal injury. Two NSAIDs were modified by incorporation of an nitroxybutyl moiety. The short-term ulcerogenic and anti-inflammatory properties of these derivatives were compared with the native NSAIDs.

Methods: Rats were given flurbiprofen, ketoprofen, or their respective derivatives, and the extent of gastric damage and effect on gastric prostaglandin E2 synthesis was assessed. The damage-promoting effects of these compounds were also compared following twice-daily administration for 1 week. Anti-inflammatory properties were examined using a carrageenan-induced paw edema model.

Results: The derivatives of flurbiprofen and ketoprofen caused significantly less short-term gastric mucosal injury at all doses tested, despite producing comparable suppression of prostaglandin synthesis. The NSAID derivatives also showed comparable anti-inflammatory activity to the native compounds. The flurbiprofen derivative inhibited collagen-induced platelet aggregation significantly more than the native NSAID. Plasma nitrate/nitrite levels increased significantly following administration of the flurbiprofen derivative, consistent with release of a nitrogen oxide.

Conclusions: Addition of a nitroxybutyl moiety to two NSAIDs markedly reduced the ability of these agents to induce short-term gastric injury but did not interfere with their ability to suppress inflammatory processes, inhibit prostaglandin synthesis, or inhibit platelet aggregation. These NSAID derivatives may therefore represent a novel class of anti-inflammatory drugs with markedly less ulcerogenic effects on the stomach.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal / adverse effects*
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
  • Cell Adhesion / physiology
  • Flurbiprofen / adverse effects
  • Flurbiprofen / analogs & derivatives
  • Flurbiprofen / pharmacology
  • Ketoprofen / adverse effects
  • Ketoprofen / pharmacology
  • Leukocytes / cytology
  • Leukocytes / physiology
  • Male
  • Nitrates / blood
  • Nitrites / blood
  • Nitrogen Oxides / pharmacology
  • Platelet Aggregation
  • Prostaglandins / metabolism
  • Rats
  • Rats, Wistar
  • Stomach Ulcer / chemically induced*
  • Stomach Ulcer / pathology
  • Stomach Ulcer / prevention & control
  • Structure-Activity Relationship


  • Anti-Inflammatory Agents, Non-Steroidal
  • Nitrates
  • Nitrites
  • Nitrogen Oxides
  • Prostaglandins
  • nitroflurbiprofen
  • Flurbiprofen
  • Ketoprofen