Many drugs' therapeutic targets and toxicity targets are in different organs. However, most of these drugs are systemically bioavailable, and as such have broad distribution throughout the body, i.e., they are often present at the same or even higher concent1ations at the organs responsible for the toxicity than that for the therapeutic effects. We proposed to design and develop drugs that will have local bioavailability in the target organ but will not be broadly distributed at high-enough concentration to illicit toxic side effects in non-targeted organs. The approach we use is to purposefully build-in structural motif that will subjected the compound to be rapidly metabolized by phase II enzymes before reaching the non-targeted organs responsible for toxicity. The current invention disclosure uses locally bioavailable COX-2 inhibitors as examples to demonstrate the principle. Our invention directly refers to the methods of preparation of locally active COX-2 inhibitors that are not systemically bioavailable, and therefore, will not cause cardiovascular toxicity. Locally bioavailable COX-2 inhibitors can be used for colon cancer prevention, precancerous lesions, intestinal inflammation-related diseases, and arthritis pain (via local injection). It is likely that the concept can be applied to additional therapeutic classes whose therapeutic target is in the intestinal lumen but wh9se toxic side effect targets are not. For example, this can apply for glucose transporter (SGLT2) inhibitors that treat diabetes, and for cholesterol absorption (Niemann-Pick Cl-like 1, NPClll protein) inhibitors that treat hyperlipidemia.