Dersalazine

BACKGROUND AND PURPOSEDersalazine sodium (DS) is a new chemical entity formed by combining, through an azo bond, a potent platelet activating factor (PAF) antagonist (UR‐12715) with 5‐aminosalicylic acid (5‐ASA). DS has been demonstrated to have anti‐inflammatory effects on trinitrobenzene sulphonic acid (TNBS)‐induced colitis in rats and recently in UC patients in phase II PoC. There is Increasing evidence that Th17 cells have an important role in the pathogenesis of inflammatory bowel disease (IBD). The aim of this study was to further characterize the anti‐inflammatory effects of DS.EXPERIMENTAL APPROACHEffect of DS (10 or 30 mg·kg−1b.i.d.) on TNBS‐induced colitis in rats was studied after 2 and 7 days with special focus on inflammatory mediators. Additionally, its anti‐inflammatory properties were analysed in two different models of dextran sodium sulphate (DSS)‐induced colitis, BALB/c and C57BL/6 mice, the latter being dependent on IL‐17.KEY RESULTSDS, when administered for 7 days, showed intestinal anti‐inflammatory effects in TNBS‐induced colitis; these effects were observed both macroscopically and through the profile of inflammatory mediators (TNF, IL‐1β, IL‐6 and IL‐17). Although the 2 day treatment with DS did not induce intestinal anti‐inflammatory effects, it was sufficient to reduce the enhanced IL‐17 expression. DS showed beneficial effects on DSS‐induced colitis in C57BL/6 mice and reduced colonic pro‐inflammatory cytokines IL‐1β, IL‐6 and IL‐17. In contrast, it did not exert intestinal anti‐inflammatory effects on DSS‐induced colitis in BALB/c mice.CONCLUSIONS AND IMPLICATIONSDS exerts intestinal anti‐inflammatory activity in different rodent models of colitis through down‐regulation of IL‐17 expression.

This paper describes the synthesis of a series of azo compounds able to deliver 5-aminosalicylic acid (5-ASA) and a potent platelet activating factor (PAF) antagonist in a colon-specific manner for the purpose of treating ulcerative colitis. We found it possible to add an amino group on the aromatic moiety of our reported 1-[(1-acyl-4-piperidyl)methyl]-1H-2-methylimidazo[4,5-c]pyridine derivatives or on British Biotech compounds BB-882 and BB-823 maintaining a high level of activity as PAF antagonist. A selected compound UR-12715 (49c) showed an IC(50) of 8 nM in the in vitro PAF-induced aggregation assay, and an ID(50) of 29 microg/kg in the in vivo PAF-induced hypotension test in normotensive rats. Through attachment of 49c to the 5-ASA via azo functionality we obtained UR-12746 (70). Pharmacokinetics experiments with [14C]-70 allow us to reach the following conclusions, critical in the design of these new prodrugs of 5-ASA. Neither the whole molecule 70 nor the carrier 49c were absorbed after oral administration of [14C]-70 in rat as was demonstrated by the absence of plasma levels of radioactivity and the high recovery of it in feces. Effective cleavage of azo bond (84%) by microflora in the colon is achieved. These facts ensure high topical concentrations of 5-ASA and 49c in the colon. Additionally, 70 exhibited a potent anticolitic effect in the trinitrobenzenesulfonic acid-induced colitis model in the rat. This profile suggests that UR-12746 (70) provides an attractive new approach to the treatment of ulcerative colitis.