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 20-fold reduced
EC50 for increasing cellular cGMP. 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.
Keywords : Phosphodiesterase, intestines, colon neoplasms