Discovery and Evaluation of Pyrazolo[3,4- d]pyridazinone as a Potent and Orally Active Irreversible BTK Inhibitor

  • ACS Med Chem Lett. 2019 Dec 11;11(10):1863-1868. doi: 10.1021/acsmedchemlett.9b00395.
Xuejun Zhang  1  2 ,  Xijun Sheng  1  2 ,  Jie Shen  1  2 ,  Shoubo Zhang  1  2 ,  Wenjie Sun  1  2 ,  Chunli Shen  3 ,  Yi Li  3 ,  Jun Wang  3 ,  Huqiang Lv  3 ,  Minghui Cui  3 ,  Yuchuan Zhu  3 ,  Lei Huang  3 ,  Dongling Hao  3 ,  Zhibo Qi  3 ,  Guanglong Sun  3 ,  Weifeng Mao  3 ,  Yan Pan  3 ,  Liang Shen  3 ,  Xin Li  3 ,  Guoping Hu  3 ,  Zhen Gong  3 ,  Shuhua Han  3 ,  Jian Li  3 ,  Shuhui Chen  3 ,  Ronghua Tu  1  2 ,  Xuehai Wang  2 ,  Chengde Wu  3
Affiliations
  • 1. Hubei Bio-Pharmaceutical Industrial Technological Institute Inc., No. 666 High Tech Avenue, East Lake High Tech Development Zone, Wuhan, Hubei 430075, China.
  • 2. Humanwell Healthcare (Group) Co., Ltd., No. 666 High Tech Avenue, East Lake High Tech Development Zone, Wuhan, Hubei 430075, China.
  • 3. Domestic Discovery Service Unit, WuXi AppTec, 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, China.
PMID: 33062165 DOI: 10.1021/acsmedchemlett.9b00395
Abstract

The identification and lead optimization of a series of pyrazolo[3,4-d]pyridazinone derivatives are described as a novel class of potent irreversible Btk inhibitors, resulting in the discovery of compound 8. Compound 8 exhibited high potency against Btk kinase and acceptable PK profile. Furthermore, compound 8 demonstrated significant in vivo efficacy in a mouse-collagen-induced arthritis (CIA) model.

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