Cyclooxygenases (COX) have been implicated in the etiology of a number of diseases, but defining the precise contribution of COXs to these diseases is challenging. Potent COX inhibitors exist, but they display off-target effects. 2'-Desmethyl derivatives of indomethacin and sulindac sulfide were synthesized that demonstrated reduced COX inhibitory activity but were inducers of peroxisome proliferator-activated receptor gamma-dependent transcription, adipocyte differentiation, or apoptosis of colon cancer cell lines. 2'-Desmethylindomethacin demonstrated gastrointestinal toxicity lower than that of indomethacin in C57BL6 mice, highlighting the importance of COX activity in maintaining gastrointestinal homeostasis and establishing that COX inhibition contributes to gastrointestinal toxicity by nonsteroidal antiinflammatory drugs. These compounds serve as useful probes of COX-dependent biology and may represent leads for antidiabetic and anticancer drugs.