2. Academic Validation
  3. Synthesis and biological evaluation of 4-(pyridin-4-oxy)-3-(3,3-difluorocyclobutyl)-pyrazole derivatives as novel potent transforming growth factor-β type 1 receptor inhibitors

Synthesis and biological evaluation of 4-(pyridin-4-oxy)-3-(3,3-difluorocyclobutyl)-pyrazole derivatives as novel potent transforming growth factor-β type 1 receptor inhibitors

  • Eur J Med Chem. 2020 Jul 15;198:112354. doi: 10.1016/j.ejmech.2020.112354.
Guofeng Xu 1,  Yan Zhang 2,  Hai Wang 2,  Zhuang Guo 2,  Xiaowei Wang 2,  Xue Li 2,  Shaohua Chang 2,  Tianwen Sun 2,  Zhuangzhuang Yu 2,  Tianwei Xu 2,  Liwen Zhao 3,  Yazhou Wang 4,  Wenying Yu 5
Affiliations

Affiliations

  • 1 State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing, 210009, People's Republic of China; Nanjing Sanhome Pharmaceutical Co. Ltd, No. 99, West Yunlianghe Road, Jiangning District, Nanjing, 210049, People's Republic of China.
  • 2 Nanjing Sanhome Pharmaceutical Co. Ltd, No. 99, West Yunlianghe Road, Jiangning District, Nanjing, 210049, People's Republic of China.
  • 3 Nanjing Sanhome Pharmaceutical Co. Ltd, No. 99, West Yunlianghe Road, Jiangning District, Nanjing, 210049, People's Republic of China. Electronic address: zhaolw@sanhome.com.
  • 4 Nanjing Sanhome Pharmaceutical Co. Ltd, No. 99, West Yunlianghe Road, Jiangning District, Nanjing, 210049, People's Republic of China. Electronic address: wangyzyf@sanhome.com.
  • 5 State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing, 210009, People's Republic of China. Electronic address: ywy@cpu.edu.cn.
PMID: 32387837 DOI: 10.1016/j.ejmech.2020.112354
Abstract

Inhibition of transforming growth factor β (TGF-β) type 1 receptor (ALK5) provides a feasible approach for the treatment of fibrotic diseases and malignant tumors. In this study, we designed and synthesized a new series of 4-(pyridin-4-oxy)-3-(3,3-difluorocyclobutyl)-pyrazole derivatives, and evaluated biologically as TGF-β type 1 receptor inhibitors. The most potent compound 15r inhibited the ALK5 Enzyme and NIH3T3 cell viability with IC50 values of 44 and 42.5 nM, respectively. Compound 15r also displayed better oral plasma exposure and excellent bioavailability than LY-3200882, and in vivo inhibited 65.7% of the tumor growth in a CT26 xenograft mouse model.

Keywords

ALK5; Antitumor activity; TGF-β inhibitor.

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