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Discovery and Evaluation of Pyrazolo[3,4-d]pyridazinone as a Potent and Orally Active Irreversible BTK Inhibitor
ACS Medicinal Chemistry Letters ( IF 4.2 ) Pub Date : 2019-12-11 , 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
ACS Medicinal Chemistry Letters ( IF 4.2 ) Pub Date : 2019-12-11 , 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
Affiliation
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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.
中文翻译：
吡唑并[3,4-d]哒嗪酮作为强效口服活性不可逆BTK抑制剂的发现和评价
一系列吡唑并[3,4- d ]哒嗪酮衍生物的鉴定和先导优化被描述为一类新型的强效不可逆BTK抑制剂，从而发现了化合物8。化合物8表现出对 BTK 激酶的高效能和可接受的 PK 特征。此外，化合物8在小鼠胶原诱导的关节炎 (CIA) 模型中显示出显着的体内功效。
更新日期：2019-12-11
中文翻译：
吡唑并[3,4-d]哒嗪酮作为强效口服活性不可逆BTK抑制剂的发现和评价
一系列吡唑并[3,4- d ]哒嗪酮衍生物的鉴定和先导优化被描述为一类新型的强效不可逆BTK抑制剂，从而发现了化合物8。化合物8表现出对 BTK 激酶的高效能和可接受的 PK 特征。此外，化合物8在小鼠胶原诱导的关节炎 (CIA) 模型中显示出显着的体内功效。
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