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.