Development of a novel hydrogen sulfide-releasing mesalamine derivative for treatment of gastrointestinal inflammation and pain

Abstract

For several years we have been designing, developing and testing novel NSAIDs for treatment of diseases such as osteoarthritis and rheumatoid arthritis. Linking an H2S-releasing moiety to an NSAID, in the majority of cases, yields a drug with comparable anti-inflammatory potency to the 'parent' NSAID, but one which produces substantially less damage and bleeding in the stomach and small intestine of laboratory animals. In the course of testing several of the NSAID derivatives, we made a surprising discovery. The derivatives made with one particular H2S-releasing moiety, 4-thiobenzamide ("TBZ"), exhibited two distinct properties from derivatives made with the other H2S-releasing moieties: an increase in the duration of activity (half-life), and an increase in potency. Moreover, the increase in potency was much more pronounced in humans than it was in mice, rats and dogs. This was first noticed during a Phase 1 trial in healthy volunteers, where suppression of COX activity with ATB-346 was much greater and long-lasting than would be expected with the naproxen component of the drug. Indeed, significant COX inhibition was observed soon after drug administration, when plasma naproxen levels were very low. Those observations were confirmed and extended in a recent Phase 2 clinical trial in patients with osteoarthritis (17). As shown in Figure 5, once daily treatment with ATB-346 (naproxen-TBZ) was very effective in reducing pain in these patients. At day 10, a reduction of 8 points on the WOMAC pain scale was observed. In contrast, similar studies with twice-daily naproxen or celecoxib have shown a reduction of only 4 points on the WOMAC pain scale (23,24).Note that the daily dose of 250 mg of ATB-346 only contains one-sixth the amount of naproxen as in the typical daily dose for treating osteoarthritis, and measurements of suppression of COX activity suggested an increase in potency over naproxen of at least 10-fold. Hypothesis: A novel H2S-releasing derivative of mesalamine, M-TBZ, will exhibit enhanced potency vs mesalamine and ATB-429 in models of colitis, enteritis and gastritis. It will also exhibit enhanced visceral analgesic activity. The systemic absorption of mesalamine from M-TBZ will be greatly decreased as compared to that of pure mesalamine. We have performed preliminary testing on a prototype molecule based on mesalamine ("M-TBZ") that is inexpensive to synthesize and, as for ATB-429, exhibits negligible systemic absorption as suggested by the presence of this orange-coloured drug in the feces. However, studies similar to those shown in Figure 1 are required to confirm and quantify this property of M-TBZ. Pilot studies have been performed in which M-TBZ produced a significant reduction in colitis severity scores and tissue myeloperoxidase activity in rats with DNBS-induced colitis. However, because of a very limited supply of this drug, the sample size per group was small (n=4) and only one time-point was examined. During the course of this visiting professorship, I would like to complete a number of proof-of-concept studies on this novel anti-inflammatory drug, M-TBZ. Two types of studies will be performed. One will be directed to determining if M-TBZ (and/or its mesalamine component) is poorly absorbed after oral administration, as was the case for ATB-429. This study will be performed in beagle dogs under the supervision of Professor de Nucci. The second, and more extensive type of study will be a thorough pre-clinical characterization of the effects of M-TBZ in several animal models of gastrointestinal inflammation and ulceration. The models will include gastric inflammation (iodoacetamide-induced); gastric ulcer healing (acetic acid-induced); enteric inflammation and ulceration (naproxen-induced); and 2 models of colonic inflammation and ulceration (dinitrobenzene sulfonic acid [DNBS] and dextran sodium sulfate- [DSS]. (AU)