A non-systemic phosphodiesterase-5 inhibitor suppresses colon
proliferation in mice
Abstract
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.