Abstract The structure–activity relationship (SAR) study of two chemotypes identified as inhibitors of the human NAD+-dependent 15-hydroxyprostaglandin dehydrogenase (HPGD, 15-PGDH) was conducted. Top compounds from both series displayed potent inhibition (IC 50< 50 nM), demonstrate excellent selectivity towards HPGD and potently induce PGE 2 production in A549 lung cancer and LNCaP prostate cancer cells.