Novel azo derivatives as prodrugs of 5-aminosalicylic acid and amino derivatives with potent platelet activating factor antagonist activity

This paper describes the synthesis of a series of azo compounds able to del iver 5-aminosalicylic acid (5-ASA) and a potent platelet activating factor (PAF) antagonist in a colon-specific manner for the purpose of treating ulc erative 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-82 3 maintaining a high level of activity as PAF antagonist. A selected compou nd UR-12715 (49c) showed an IC50 of 8 nM in the in vitro PAF-induced aggreg ation assay, and an ID50 of 29 mug/kg in the in vivo PAF-induced hypotensio n test in normotensive rats. Through attachment of 49c to the 5-ASA via azo functionality we obtained UR-12746 (70). Pharmacokinetics experiments with [C-14]-70 allow us to reach the following conclusions, critical in the des ign of these new prodrugs of 5-ASA. Neither the whole molecule 70 nor the c arrier 49c were absorbed after oral administration of [C-14]-70 in rat as w as demonstrated by the absence of plasma levels of radioactivity and the hi gh recovery of it in feces. Effective cleavage of azo bond (84%) by microfl ora in the colon is achieved. These facts ensure high topical concentration s of 5-ASA and 49c in the colon. Additionally, 70 exhibited a potent antico litic effect in the trinitrobenzenesulfonic acid-induced colitis model in t he rat. This profile suggests that UR-12746 (70) provides an attractive new approach to the treatment of ulcerative colitis.