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. eCollection 2020 Oct 8.

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

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

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.

KEYWORDS: 

BTK inhibitor, irreversible, pyridazinone, enzymatic potency, rheumatoid arthritis