title: A double prodrug system for colon targeting of benzenesulfonamide COX-2 inhibitors.
abstract: The design, synthesis and delivery potential of a new type of benzenesulfonamide cyclo-oxygenase-2 (COX-2) inhibitor prodrug is investigated using celecoxib. The approach involves a double prodrug that is activated first by azoreductases and then by cyclization triggering drug release. We studied the intramolecular aminolysis of the acylsulfonamide. The cyclization was surprisingly rapid at physiological pH and very fast at pH 5. The prodrug is activated specifically under conditions found in the colon but highly stable in the presence of human and rodent intestinal extracts. Finally, the prototype with celecoxib was transported much more slowly in the Caco-2 transepithelial model than the parent. The design therefore shows significant promise for the site specific delivery of benzenesulfonamide COX-2 inhibitors to the colon.
authors: School of Pharmacy and Pharmaceutical Sciences, Trinity College, Dublin 2, Ireland.
authors: Juan F Marquez
authors: JF
authors: Ruiz
authors: Kinga
authors: K
authors: Kedziora
authors: Brian
authors: B
authors: Keogh
authors: Jacqueline
authors: J
authors: Maguire
authors: Mary
authors: M
authors: Reilly
authors: Henry
authors: H
authors: Windle
authors: Dermot P
authors: DP
authors: Kelleher
authors: John F
authors: JF
authors: Gilmer
mesh_terms: D000818:Animals; D018938:Caco-2 Cells; D000068579:Celecoxib; D003016:Clostridium perfringens / Q000201:enzymology; D003106:Colon / Q000378:metabolism* / Q000382:microbiology; D003110:Colonic Neoplasms / Q000188:drug therapy; D003500:Cyclization; D051546:Cyclooxygenase 2 / Q000378:metabolism; D052246:Cyclooxygenase 2 Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics*; D015195:Drug Design; D006801:Humans; D009247:NADH, NADPH Oxidoreductases / Q000378:metabolism; D009601:Nitroreductases; D011355:Prodrugs / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics*; D011720:Pyrazoles / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics*; D051381:Rats; D013449:Sulfonamides / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics*; D000096926:Benzenesulfonamides
chemical_list: D000068579:Celecoxib; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D009247:NADH, NADPH Oxidoreductases; D009601:Nitroreductases; D011355:Prodrugs; D011720:Pyrazoles; D013449:Sulfonamides; D000096926:Benzenesulfonamides; C021106:azoreductase