2. Academic Validation
  3. Successive structural optimization of Ziritaxestat culminates in the discovery of orally bioavailable and in vivo potent imidazothiadiazole derivative for treating ATX-driven diseases

Successive structural optimization of Ziritaxestat culminates in the discovery of orally bioavailable and in vivo potent imidazothiadiazole derivative for treating ATX-driven diseases

  • Eur J Med Chem. 2025 Oct 5:295:117769. doi: 10.1016/j.ejmech.2025.117769.
Henian Wang 1,  Yulei Liu 1,  Qinlong Xu 2,  Gaofeng Lin 2,  Li Shao 2,  Jiajia Mo 2,  Jiaming Li 3,  Zhaoxing Chu 4,  Xiaodong Ma 5
Affiliations

Affiliations

  • 1 College of Pharmacy, Anhui University of Chinese Medicine, Hefei, 230012, China.
  • 2 Hefei Institute of Pharmaceutical Industry Company, Ltd., Hefei, 230088, China.
  • 3 College of Pharmacy, Anhui University of Chinese Medicine, Hefei, 230012, China; Institute of Medicinal Chemistry, Anhui Academy of Chinese Medicine, Hefei, 230012, China; Anhui Province Key Laboratory of Bioactive Natural Products, Hefei, 230012, China. Electronic address: lijiam2011@126.com.
  • 4 Hefei Institute of Pharmaceutical Industry Company, Ltd., Hefei, 230088, China. Electronic address: chuzhaoxing@163.com.
  • 5 College of Pharmacy, Anhui University of Chinese Medicine, Hefei, 230012, China; Institute of Medicinal Chemistry, Anhui Academy of Chinese Medicine, Hefei, 230012, China; Anhui Province Key Laboratory of Bioactive Natural Products, Hefei, 230012, China. Electronic address: tgmxd1988@ahtcm.edu.cn.
PMID: 40413987 DOI: 10.1016/j.ejmech.2025.117769
Abstract

Herein, we communicate our medicinal chemistry campaign culminating in the discovery of imidazothiadiazole-based ATX inhibitor with oral bioavailability and potent in vivo efficacy. During our successive structural modification of Ziritaxestat, an ATX inhibitor advanced into phase III clinical trial, a total of 25 analogs have been designed and synthesized for improving its potency. Among them, 9 compounds exhibited single-digit nanomolar ATX inhibitory activity (IC50 = 2.54-9.01 nM), which was remarkably enhanced over Ziritaxestat (IC50 = 29.9 nM). In particular, compound 25, an imidazothiadiazole derivative that incorporated deuterated N-methyl for boosting metabolic stability, displayed an oral bioavailability of 27.1 %. In air pouch model of inflammation, it exerted superior in vivo efficacy to that of Ziritaxestat, as revealed by the more dramatic suppression of LPA secretion resulted from the treatment with 25. Moreover, 25 demonstrated promising therapeutic efficacy against bleomycin-induced systemic sclerosis in mice. Attributed to its attractive in vitro and in vivo performance in battling ATX-related diseases, 25 deserves further development as a potential candidate.

Keywords

ATX; Imidazothiadiazole; In vivo efficacy; Inhibitory activity; Oral bioavailability.

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