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

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

  • Bioorg Med Chem Lett. 2024 Oct 28:114:130006. doi: 10.1016/j.bmcl.2024.130006.
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

Affiliations

  • 1 Data Convergence Drug Research Center, Korea Research Institute of Chemical Technology, Yuseong-gu, Daejeon 34114, Republic of Korea.
  • 2 Data Convergence Drug Research Center, Korea Research Institute of Chemical Technology, Yuseong-gu, Daejeon 34114, Republic of Korea; Department of Medicinal Chemistry and Pharmacology, KRICT School, University of Science and Technology, Yuseong-gu, Daejeon 34113, Republic of Korea.
  • 3 Data Convergence Drug Research Center, Korea Research Institute of Chemical Technology, Yuseong-gu, Daejeon 34114, Republic of Korea; Graduate School of New Drug Discovery and Development, Chungnam National University, Yuseong-gu, Daejeon 34134, Republic of Korea.
  • 4 Data Convergence Drug Research Center, Korea Research Institute of Chemical Technology, Yuseong-gu, Daejeon 34114, Republic of Korea; Department of Medicinal Chemistry and Pharmacology, KRICT School, University of Science and Technology, Yuseong-gu, Daejeon 34113, Republic of Korea. Electronic address: ksoh@krict.re.kr.
PMID: 39477127 DOI: 10.1016/j.bmcl.2024.130006
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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