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 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.