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Azo-reductase activated budesodine prodrugs for colon targeting
Authors:Juan F Marquez Ruiz  Kinga Kedziora  Mary O’Reilly  Jacqueline Maguire  Brian Keogh  Henry Windle  Dermot P Kelleher  John F Gilmer
Institution:1. School of Pharmacy and Pharmaceutical Sciences, Trinity College, Dublin 2, Ireland;2. School of Medicine, Trinity College, Dublin 2, Ireland;3. Opsona Therapeutics LTD, Trinity Centre for Health Sciences, Institute of Molecular Medicine, St James’s Hospital, Dublin 8, Ireland
Abstract:Budesodine is a synthetic glurocorticoid that undergoes substantial first pass metabolism, limiting systemic exposure. Its use in treatment of inflammatory bowel disease would benefit from a targeting strategy that could lead to a local topical effect, improving safety and increasing anti-inflammatory efficacy. A two-step prodrug strategy involving azoreduction/cyclization that we developed previously for prednisolone is here applied with some variations to budesonide. The budesodine prodrugs were tested using an in vitro azoreductase assay simulating human colonic microflora. The kinetics of amino steroid ester cyclization and its pH dependence was also evaluated. The stability of the prodrugs systems in simulated human duodenal and gastric fluid was evaluated to determine the likelihood of intact intestinal transit. The propionic acid derived prodrug 3 undergoes rapid activation by Clostridium perfingens and its putative reduction product cyclizes with acceptable rapidity when synthesized independently. These properties of 3 suggest that it has potential in management of ulcerative colitis.
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