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. 2024 Dec 1:114:130006.
doi: 10.1016/j.bmcl.2024.130006. Epub 2024 Oct 28.

Design, synthesis and evaluation of 3-(2-(substituted benzyloxy)benzylidene) pyrrolidine-2,5-dione derivatives for novel ATX inhibitor

Seung Hyeong Lee  1 , Su Jin Park  2 , Mi Young Lee  1 , Jun Young Choi  1 , Woo Dae Jang  2 , Jidon Jang  1 , Jeong Hyun Lee  3 , Chae Jo Lim  1 , Kwang-Seok Oh  4
Affiliations

Design, synthesis and evaluation of 3-(2-(substituted benzyloxy)benzylidene) pyrrolidine-2,5-dione derivatives for novel ATX inhibitor

Seung Hyeong Lee et al. Bioorg Med Chem Lett. .

Abstract

Autotaxin (ATX) has emerged as a promising therapeutic target for liver diseases. In this study, we identified potential drug candidates through in silico high-throughput screening. Subsequently, we synthesized a series of small molecules, specifically KR-40795 (2c), a pyrrolidine-2,5-dione-based analogue that binds to the allosteric tunnel and hydrophobic pocket of ATX. This compound was designed to inhibit the enzymatic activity of ATX for the treatment of liver diseases. The inhibitory potency of KR-40795 was evaluated using a biochemical assay that measured the hydrolysis of a specific substrate (FS-3). Notably, KR-40795 demonstrated significant inhibition of both collagen formation and lipid accumulation in liver cells, suggesting its potential as a therapeutic agent for liver diseases, particularly fibrosis and steatosis.

Keywords: Autotaxin; Inhibition; Liver fibrosis; Pyrrolidine-2,5-dione; Steatosis.

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Conflict of interest statement

Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Kwang-seok Oh acknowledges financial support from the National Research Foundation of Korea and the Korea Research Institute of Chemical Technology. Any additional authors declare that they have no competing financial interests or personal relationships that could have influenced the work presented in this paper.

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