A double prodrug system for colon targeting of benzenesulfonamide COX-2 inhibitors

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:21

Article

Ruiz, Juan F. Marquez¹  Kedziora, Kinga¹  Keogh, Brian³  Maguire, Jacqueline³  Reilly, Mary³  Windle, Henry²  Kelleher, Dermot P.²  Gilmer, John F.¹ 

[1] Trinity Coll Dublin, Sch Pharm & Pharmaceut Sci, Dublin 2, Ireland

[2] Trinity Coll Dublin, Sch Med, Dublin 2, Ireland

[3] St James Hosp, Opsona Therapeut Ltd, Trinity Ctr Hlth Sci, Inst Mol Med, Dublin 8, Ireland

关键词: COX-2 inhibitor;    Colon cancer;    Celecoxib;    Azoreductase;    Cyclization;   

DOI  :  10.1016/j.bmcl.2011.09.071

来源: Elsevier

【 摘 要 】

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. (C) 2011 Elsevier Ltd. All rights reserved.

【 授权许可】

Free