Design, synthesis, and pharmacological effects of a cyclization-activated steroid prodrug for colon targeting in inflammatory bowel disease.
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.
Ruiz
Juan F Márquez
JF
School of Pharmacy and Pharmaceutical Sciences, Trinity College, Dublin 2, Ireland.
Radics
Gabor
G
Windle
Henry
H
Serra
Hugo O
HO
Simplício
Ana Luísa
AL
Kedziora
Kinga
K
Fallon
Padraic G
PG
Kelleher
Dermot P
DP
Gilmer
John F
JF
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
D000305:Adrenal Cortex Hormones; D004337:Drug Carriers; D004952:Esters; D011355:Prodrugs