Approximately 50,000 people will die from colorectal cancer (CRC) in the United States this year due to the late stage at diagnosis where treatments are largely ineffective. Primary prevention of CRC is therefore very important for high-risk patients. Chemoprevention agents are needed for CRC but nothing has been approved for this purpose. Extensive preclinical and epidemiological evidence show great promise for repurposing phosphodiesterase-5 inhibitors (PDE5i) for CRC chemoprevention. Barriers to this application of PDE5i include the numerous side effects and drug-drug interactions resulting from systemic delivery that would reduce compliance in an otherwise healthy population. Our goal is to develop novel gut-targeted PDE5i for CRC chemoprevention in people at high risk. Our central hypothesis is that polar analogs of sildenafil will make ideal non-systemic agents for developing into drugs for the primary chemoprevention of CRC in humans. Our objectives are (1) To gain detailed information about the pharmacokinetic properties of malonyl- and boronyl-sildenafil in vitro, and (2) to determine whether these analogs can prevent colon cancer in a mouse model of sporadic CRC. We will test our central hypothesis and thereby accomplish the objectives of this project by completing the following aims: Aim 1. Test the hypothesis that polar analogs of sildenafil behave as gut-epithelium targeted PDE5i. Aim 2. To test the hypothesis that polar analogs of sildenafil can inhibit colon cancer in mice. By providing detailed pharmacokinetic information and proof of principle in a preclinical CRC model, our project's scientific impact will be to clear the path for further development of our polar PDE5i analogs as first in class drugs for the primary chemoprevention of CRC.