15-hydroxyprostaglandin dehydrogenase (15-PGDH; HPGD) is the key enzyme for the inactivation of prostaglandins, and thus regulates processes such as inflammation or proliferation. The anabolic pathways of prostaglandins are well-characterized, especially with respect to regulation of the cyclooxygenase (COX) enzymes. In comparison, little is known about downstream events, including functional interaction of prostaglandin-processing and metabolizing enzymes, as well as the function of prostaglandin receptors. To date, the only known strong inhibitors belong to the family of thiazolinedines that affect other pathways, notably by binding to peroxisome proliferator-activated receptor (PPAR)γ. The present study discloses the discovery and characterization of a potent and competitive HPGD inhibitor that is selective within the dehydrogenase family, ML147 (CID-3245059). It also discloses two high-affinity and uncompetitive HPGD inhibitors that are selective within the dehydrogenase family, ML148 (CID-3243760) and ML149 (CID-2331284). These small molecule probes represent the most potent and selective inhibitors of 15-HPGD reported thus far.