Synthesis and SAR of thiazolidinedione derivatives as 15-PGDH inhibitors

Bioorganic & Medicinal Chemistry
Ying WuHoon Cho

Abstract

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.

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Citations

Jan 1, 2013·International Journal of Medicinal Chemistry·Ravinder Singh BhattiJagir S Sandhu
Dec 3, 2014·Prostaglandins, Leukotrienes, and Essential Fatty Acids·Yu Lan PiaoHoon Cho
Apr 23, 2015·Prostaglandins, Leukotrienes, and Essential Fatty Acids·Seung Yong SeoSung Chul Lim
Jun 28, 2018·Archives of Pharmacal Research·So Hee ParkHoon Cho
Jan 2, 2021·European Journal of Medicinal Chemistry·Ruifang JiaXinyong Liu
Sep 23, 2014·Journal of Medicinal Chemistry·Jessamyn I PerlmutterDaniel P Flaherty

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