Synthesis and SAR of thiazolidinedione derivatives as 15-PGDH inhibitors

Prostaglandins have a short life in vivo because they are metabolized rapidly by oxidation to 15-ketoprostaglandins catalyzed by a cytosolic Enzyme known as NAD(+)-dependent 15-hydroxyprostaglandin dehydrogenase (15-PGDH). Previously, CT-8, a thiazolidinedione analogue, was found to be a potent inhibitor of 15-PGDH. Structure-activity analysis indicated that the N-methylation of thiazolidine-2,4-dione, CT-8, abolished the inhibitory activity, whereas the introduction of an ethyl hydroxyl group at amine in CT-8 still had a good inhibitory effect. Based on the structures of the thiazolidinediones analogues and inhibitory activity, a range of benzylidene thiazolidinedione derivatives were synthesized with different substituents on the phenyl ring and their inhibitory activity was evaluated. Replacement of the cyclohexylethyl group of CT-8 with the hetero five-member ring increased the inhibitory potency. However, replacement of the cyclohexylethyl group with a hetero six-member ring decreased the inhibitory potency significantly. It was found that compound 2 (5-(4-(2-(thiophen-2-yl)ethoxy)benzylidene)thiazolidine-2,4-dione) was the most potent inhibitor that was effective in the nanomolar range.