title: Design, synthesis, and pharmacological effects of a cyclization-activated steroid prodrug for colon targeting in inflammatory bowel disease.
abstract: 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.
authors.affiliation: School of Pharmacy and Pharmaceutical Sciences, Trinity College, Dublin 2, Ireland.
authors.forename: Juan F Márquez
authors.initials: JF
authors.lastname: Ruiz
authors.forename: Gabor
authors.initials: G
authors.lastname: Radics
authors.forename: Henry
authors.initials: H
authors.lastname: Windle
authors.forename: Hugo O
authors.initials: HO
authors.lastname: Serra
authors.forename: Ana Luísa
authors.initials: AL
authors.lastname: Simplício
authors.forename: Kinga
authors.initials: K
authors.lastname: Kedziora
authors.forename: Padraic G
authors.initials: PG
authors.lastname: Fallon
authors.forename: Dermot P
authors.initials: DP
authors.lastname: Kelleher
authors.forename: John F
authors.initials: JF
authors.lastname: Gilmer
mesh_terms: D000305:Adrenal Cortex Hormones / Q000008:administration & dosage*; D000818:Animals; D001419:Bacteria / Q000378:metabolism; D003106:Colon / Q000378:metabolism* / Q000382:microbiology; D003500:Cyclization; D004337:Drug Carriers / Q000138:chemical synthesis*; D016503:Drug Delivery Systems; D004952:Esters; D015212:Inflammatory Bowel Diseases / Q000188:drug therapy*; D007408:Intestinal Absorption / Q000187:drug effects; D051379:Mice; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism
chemical_list: D000305:Adrenal Cortex Hormones; D004337:Drug Carriers; D004952:Esters; D011355:Prodrugs