Design, Synthesis, and Pharmacological Effects of a Cyclization-Activated Steroid Prodrug for Colon Targeting in Inflammatory Bowel Disease

作者：Ruiz Juan F Marquez; Radics Gabor; Windle Henry; Serra Hugo O; Simplicio Ana Luisa; Kedziora Kinga; Fallon Padraic G; Kelleher Dermot P; Gilmer John F^*

来源：Journal of Medicinal Chemistry, 2009, 52(10): 3205-3211.

DOI：10.1021/jm8016317

Glucocorticoids are used in the treatment of inflammatory bowel disease. A limitation to their use is that they undergo absorption from the GIT before reaching the colon causing severe systemic side effects. We report here on a novel prodrug approach to targeting corticosteroids to the colon. The design involves attaching a 21-ester group that suppresses absorption during transit to the colon. The prodrug is designed to be primed by colonic microflora liberating an amino ester that cyclizes releasing the steroid. One of the prodrugs 5b was as efficacious as prednisolone in the murine DSS model but did not cause thymic atrophy, a marker for systemic steroid effects.

• 出版日期2009-5-28