ATB-337

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Background

ATB-337 is a hybrid molecule of an H2S donor and the NSAID diclofenac [1].Hydrogen sulfide (H2S) is a newly recognized signaling molecule with potent cytoprotective actions. Hydrogen sulfide has been involved in mediating many physiological processes, such as the maintenance of gastrointestinal mucosal defense and repair. Hydrogen sulfide also exerts many anti-inflammatory effects, including inhibition of leukocyte adherence to the vascular endothelium and leukocyte migration to sites of inflammation [2]. Oral administration of ATB-337 did not produce any hemorrhagic erosions. Oral administration of an equimolar dose of ATB-337 produced > 90% less small intestinal damage and showed no significant effect on the hematocrit. In rats, administration of ATB-337 (50 μmol/kg) showed no significant effect on leukocyte adherence. Oral administration of ATB-337 significantly increased plasma levels of H2S by > 40%. In a rat air pouch model, ATB-337 (1 μmol/kg) suppressed COX-2 activity. In the rat, ATB-337 inhibited thromboxane synthesis. ATB-337 suppressed arachidonic acid–induced human platelet aggregation. Pretreatment with ATB-337 (10 μmol/kg) reduced paw swelling. ATB-337 generated ～12nmol/min of H2S when it was incubated in buffer.

[1] Wallace J L, Caliendo G, Santagada V, et al. Gastrointestinal safety and anti-inflammatory effects of a hydrogen sulfide–releasing diclofenac derivative in the rat[J]. Gastroenterology, 2007, 132(1): 261-271.
[2] Wallace J L. Physiological and pathophysiological roles of hydrogen sulfide in the gastrointestinal tract[J]. Antioxidants & redox signaling, 2010, 12(9): 1125-1133.