Markedly reduced toxicity of a hydrogen sulphide‐releasing derivative of naproxen (ATB‐346)

Abstract

Background and purpose:Hydrogen sulphide is an important mediator of gastric mucosal defence. The use of non-steroidal anti-inflammatory drugs continues to be limited by their toxicity, particularly in the upper gastrointestinal tract. We evaluated the gastrointestinal safety and anti-inflammatory efficacy of a novel hydrogen sulphide-releasing derivative of naproxen, ATB-346 [2-(6-methoxy-napthalen-2-yl)-propionic acid 4-thiocarbamoyl-phenyl ester]. Experimental approach: The ability of ATB-346 versus naproxen to cause gastric damage was evaluated in healthy rats and in rats with compromised gastric mucosal defence. Effects on the small intestine and on the healing of ulcers were also assessed. The ability of ATB-346 to inhibit cyclooxygenase-1 and 2 and to reduce inflammation in vivo was also evaluated. Key results: ATB-346 suppressed gastric prostaglandin E2 synthesis as effectively as naproxen, but produced negligible damage in the stomach and intestine. In situations in which the gastric mucosa was rendered significantly more susceptible to naproxen-induced damage (e.g. ablation of sensory afferent nerves, inhibition of endogenous nitric oxide or hydrogen sulphide synthesis, co-administration with aspirin, antagonism of KIR6.x channels), ATB-346 did not cause significant damage. Unlike naproxen and celecoxib, ATB-346 accelerated healing of pre-existing gastric ulcers. In a mouse airpouch model, ATB-346 suppressed cyclooxygenase-2 activity and inhibited leukocyte infiltration more effectively than naproxen. ATB-346 was as effective as naproxen in adjuvant-induced arthritis in rats, with a more rapid onset of activity. Unlike naproxen, ATB-346 did not elevate blood pressure in hypertensive rats. Conclusions and implications: ATB-346 exhibits anti-inflammatory properties similar to naproxen, but with substantially reduced gastrointestinal toxicity.

Arylthioamides as H2S Donors: l-Cysteine-Activated Releasing Properties and Vascular Effects in Vitro and in Vivo

“…19,20 In this work, a small library of arylthioamides (compounds 1−12, Chart 1) was easily prepared through suitable synthetic routes and evaluated for their H 2 S-releasing properties. The phydroxybenzothioamide 1 19,20 was selected as lead compound to build the library by inserting a number of modifications on the aromatic moiety: (i) introduction of different groups (Cl, F, CF 3 , NO 2 , and CH 3 ) at the 2-and/or 5-position of the phenyl ring (2−6); (ii) replacement of the 4-hydroxy group with an amino moiety (7); and (iii) replacement of the phenyl ring with electron poor or electron rich heterocycles such as pyridine (8) and piperazine (9), or furane (10), thiophene (11), and indole (12), respectively (Chart 1). Finally, compound 1 was submitted to further experimental protocols aimed to evaluate the vasorelaxing effects on rat aortic rings, the membrane hyperpolarizing activity on human vascular smooth muscle (VSM) cells and the effects on the blood pressure of normotensive rats.…”

“…Compound 1 was selected for further pharmacological studies on the basis of the following issues: (i) 1 showed a thiol-dependent H 2 S-releasing profile; (ii) although it has been already reported as a H 2 S-releasing side-chain in naproxen analogues endowed with reduced toxicity, 19,20 its H 2 S-mediated cardiovascular effects have not been yet specifically investigated.…”

The Role of Capsaicin-Sensitive Afferent Nerves in Gastric Mucosal Protection Initiated Centrally or Peripherally under Experimental Conditions

“…On the other hand, exogenous H 2 S donors can increase the resistance of the gastric mucosa to injury induced by NSAIDs [34].…”

Hydrogen Sulfide: A Rescue Molecule for Mucosal Defence and Repair

“…Inhibition of endogenous H 2 S synthesis increases the susceptibility of the mucosa to damage induced by nonsteroidal anti-inflammatory drugs (NSAIDs), for example [6,7]. On the other hand, exogenous H 2 S donors can increase the resistance of the mucosa to injury [5][6][7].…”

“…Inhibition of endogenous H 2 S synthesis increases the susceptibility of the mucosa to damage induced by nonsteroidal anti-inflammatory drugs (NSAIDs), for example [6,7]. On the other hand, exogenous H 2 S donors can increase the resistance of the mucosa to injury [5][6][7]. Moreover, H 2 S synthesis is markedly up-regulated after mucosal injury occurs, and it contributes significantly to promoting the healing of the injured tissue [8,9].…”