The Development of Locally Bioavailable COX-2 Inhibitors




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Objective: The effectiveness of the selective COX-2 inhibitors in colorectal cancer chemoprevention has been demonstrated in previous studies. However, these drugs are not safe agents to patients due to their toxicity in the cardiovascular system. The long-term goal in this project is to develop new selective COX-2 inhibitors which can be used as effective and safe agents for colorectal cancer chemoprevention in human. The objective in the current studies is to develop a series of new compounds which are able to inhibit colonic COX-2 activity but not systemically bioavailable. Methods: The new compounds were designed by using celecoxib as the template. Their inhibitory effects on COX-2 activity were studied in cell-based assays or by employing recombinant human COX-2 enzyme. The metabolic properties of the new compounds were characterized by in vitro tools and models before pharmacokinetics studies were conducted in rats. Among all the new compounds, the inhibitory effect of the lead compound 6a1 on colonic COX-2 activity was then confirmed in inflamed rat colon by in situ perfusion. During the perfusion, blood and bile samples from rats were also collected for studying the absorption, metabolism and excretion of 6a1 in rats. The relevant studies were also conducted with celecoxib to show the differences between celecoxib and the locally bioavailable COX-2 inhibitors. Results: 8 new compounds with phenolic groups in their structures were successfully designed, synthesized and purified. In the cell-based assays and by employing human recombinant COX-2 enzymes, the new inhibitors were confirmed as COX-2 inhibitors, although they were less potent than celecoxib. In the in vitro characterization, some of the new compounds were very efficiently conjugated by phase II enzymes with the conjugation rates largely depended on the phenolic group species. A pharmacokinetics study in rats demonstrated the low oral bioavailability of 6a1, which was selected as the lead compound among the new compounds based their inhibitory effects on COX-2 activity and in vitro conjugation rates. When the inflamed rat colon was perfused with 70 µM 6a1, an inhibitory effect on colonic COX-2 activity was observed to be similar with that in the perfusion with 1 µM celecoxib. The blood concentration of 6a1 was lower than its IC50 on COX-2 activities during the perfusion, due to the extensive first-pass metabolism and excretion of 6a1 in liver. In contrast, the blood concentration of celecoxib in the systemic circulation was > 10-fold higher than its IC50. Conclusion: We successfully developed several new COX-2 inhibitors which were effective to inhibit COX-2 activity in inflamed rat colon but rapidly metabolized and excreted in liver. For these new compounds, the extensive first-pass metabolism in liver resulted in a poor oral bioavailability and extremely low blood concentrations in the systemic circulation, reducing or avoiding the exposure of the cardiovascular systems. Compared with celecoxib, the locally bioavailable COX-2 inhibitors are more promising to be developed as safe agents in colorectal cancer prevention.



Cyclooxygenase-2 inhibitor, Drug metabolism, Excretion, First-pass effect, Pharmacokinetics