The steroid prodrug OPN-501 has optimal drug release characteristics for colon targeting because of a kinetic advantage of a six-membered ring formation in the aminolysis reactions of anilides. The results are relevant to the development of OPN-501 but also to cyclization strategies in prodrug design especially for colon targeting.
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.
The design, synthesis and delivery potential of a new type of benzenesulfonamide cyclooxygenase-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.Colorectal cancer is the third leading cause of cancer-related death in the western world with incidence in the range 25-35 per 100,000. 1 Most colonic cancers are preceded by the development of small benign colonic polyps which may take several years to accumulate the mutations required for frank malignant change. The disease is incurable in its later stages and there is an urgent need for new therapies and chemopreventative agents.Colorectal cancer rates are reduced in patient groups chronically using aspirin or other cyclo-oxygenase (COX) inhibitory drugs. 2 The role of COX-2 in the aetiology and progression of the disease is well characterized and the enzyme is an important pharmacological target. [3][4][5][6][7] The COX-2 inhibitor celecoxib (Celebrex) was approved by the FDA (1999) as add-on therapy for patients with familial adenomatous polypsosis (FAP, 400 mg BID). Subsequent randomized clinical trials affirmed the validity of celecoxib in controlling polyp progression. In the Adenoma Prevention with Celecoxib Trial (APC), which recruited very high risk patients, high dose celecoxib (800 mg) was associated with a 45% reduction in adenoma recurrence. The APC trial is however usually remembered for the discovery of an increase in risk of adverse thrombotic events in the celecoxib treatment group, which had significance far beyond the trial. Clinical evidence supporting a class effect soon followed and the most selective COX-2 inhibitors were withdrawn from the market. Unopposed systemic COX-2 inhibition is now widely accepted to increase the risk of a cardiovascular event. 8 Accordingly, COX-2 inhibitors are indicated in only the very highest risk FAP patients.Colorectal targeting of COX-2 inhibitors is considered a promising strategem for reducing systemic exposure while focusing the beneficial COX-2 inhibitory effects on the relevant tissue. 9-13 Approaches so far have relied on formulations for local drug release.In this context it is notable that there are a number of clinically used azo-prodrugs of 5-amino salicylic acid (5-ASA) for treating inflammatory bowel disease (IBD) that act by locally releasing the drug, reducing systemic exposure and intestinal metabolism.Azoprodru...
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