Phosphodiesterase-5 inhibitors (PDE5i) are under investigation for repurposing for colon cancer prevention. A drawback to conventional PDE5i are their side-effects and drug–drug interactions. We designed an analog of the prototypical PDE5i sildenafil by replacing the methyl group on the piperazine ring with malonic acid to reduce lipophilicity, and measured its entry into the circulation and effects on colon epithelium. This modification did not affect pharmacology as malonyl-sildenafil had a similar IC50 to sildenafil but exhibited an almost 20-fold reduced EC50 for increasing cellular cGMP. Using an LC-MS/MS approach, malonyl-sildenafil was negligible in mouse plasma after oral administration but was detected at high levels in the feces. No bioactive metabolites of malonyl-sildenafil were detected in the circulation by measuring interactions with isosorbide mononitrate. The treatment of mice with malonyl-sildenafil in the drinking water resulted in a suppression of proliferation in the colon epithelium that is consistent with results previously published for mice treated with PDE5i. A carboxylic-acid-containing analog of sildenafil prohibits the systemic delivery of the compound but maintains sufficient penetration into the colon epithelium to suppress proliferation. This highlights a novel approach to generating a first-in-class drug for colon cancer chemoprevention.

Background and Purpose: Phosphodiesterase-5 inhibitors (PDE5i) are under investigation for repurposing as an intervention for colon cancer prevention. A drawback to conventional PDE5i are side-effects and drug-drug interactions that would be poorly tolerated when taken on a chronic basis for prevention. Experimental Approach: We designed an analog of the prototypical PDE5i sildenafil by replacing the methyl group on the piperazine ring with malonic acid to reduce lipophilicity and measured its entry into the circulation and effects on colon epithelium. Key Results: This modification did not affect pharmacology as malonyl-sildenafil had a similar IC50 to sildenafil (6.5 nM vs 7.5 nM respectively) but exhibited almost 100-fold reduced cell entry compared to sildenafil. Using an LC-MS/MS approach, doses of malonyl-sildenafil up to 36 mg/kg were barely detectable in mouse plasma after oral administration but was detected at high levels in the feces. This contrasted with sildenafil that was detected in the plasma but not in the feces. No bioactive metabolites of malonyl-sildenafil were detected in the circulation by measuring interactions with isosorbide mononitrate. Treatment of mice with malonyl-sildenafil in the drinking water for 8 days was well-tolerated and resulted in a suppression of proliferation in the colon epithelium that is consistent with results published previously for mice treated with PDE5i. Conclusion and Implications: A carboxylic acid-containing analog of sildenafil prohibits systemic delivery of the compound but maintains sufficient penetration into the colon epithelium to suppress proliferation. This highlights a novel approach to generate a first in class drug for colon cancer chemoprevention.

Phosphodiesterase 5 inhibitors (PDE5i) are under investigation for potential repurposing as an intervention for colon cancer prevention. A drawback to conventional drugs in this class are drug-drug interactions and side-effects and that would be poorly tolerated when taken on a chronic basis for prevention. To address this issue we designed an analog of the prototypical PDE5i sildenafil by replacing the methyl group on the piperazine ring with malonic acid to reduce lipophilicity. This modification did not affect pharmacology as malonyl-sildenafil had an IC50 of 1.8 nM, but exhibited almost 100-fold reduced cell entry compared to sildenafil. Using an LC-MS/MS approach, malonyl-sildenafil was undetectable in mouse plasma 1 hour after gavage, even at a dose up to 36 mg/kg, but was readily detected in the feces collected 2-4 hours after administration. This contrasted with sildenafil that was detected in the plasma, but not in the feces. While sildenafil exhibited the established Cmax at 1-2 hr, malonyl sildenafil was not detected in the plasma up to 24 hr after an oral dose of 9 mg/kg, but continued to be shed at high levels in the feces for up to 8 hrs. Treatment of mice with malonyl-sildenafil in the drinking water for 8 days was well-tolerated, and resulted in a suppression of proliferation in the colon epithelium that is consistent with results published previously for mice treated with PDE5i. Taken together, the results demonstrate that a carboxylic acid-containing analog of sildenafil prohibits systemic delivery but maintains sufficient penetration into the colon epithelium to suppress proliferation. This highlights a novel approach to generate a first in class drug for colon cancer chemoprevention. Citation Format: Bianca N. Islam, Avelina Lee, Iryna Lebedyeva, Darren D. Browning. A non-systemic phosphodiesterase-5 inhibitor for colon cancer prevention [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1417.

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