具有吡咯并[2,3-d]嘧啶骨架的新型布鲁顿酪氨酸激酶（BTK）抑制剂的发现。
Discovery of novel Bruton's tyrosine kinase (BTK) inhibitors bearing a pyrrolo[2,3-d]pyrimidine scaffold.
作者信息
Zhao Xinge, Huang Wei, Wang Yazhou, Xin Minhang, Jin Qiu, Cai Jianfeng, Tang Feng, Zhao Yong, Xiang Hua
机构信息
Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, No. 24, Tongjiaxiang, Nanjing 210009, PR China; Jiangsu Simcere Pharmaceutical Co. Ltd., Jiangsu Key Laboratory of Molecular Targeted Antitumor Drug Research, No 699-18, Xuan Wu District, Nanjing 210042, PR China.
Key Laboratory of Pesticide and Chemical Biology, Ministry of Education, College of Chemistry, Central China Normal University, No 152, Luoyu Road, Wuhan 430079, PR China; Jiangsu Simcere Pharmaceutical Co. Ltd., Jiangsu Key Laboratory of Molecular Targeted Antitumor Drug Research, No 699-18, Xuan Wu District, Nanjing 210042, PR China.
出版信息
Bioorg Med Chem. 2015 Feb 15;23(4):891-901. doi: 10.1016/j.bmc.2014.10.043. Epub 2014 Nov 6.
A series of novel reversible BTK inhibitors was designed based on the structure of the recently reported preclinical drug RN486. Knowledge of the binding mode of RN486 led to the design of new inhibitors that utilized pyrrolo[2,3-d]pyrimidine to conformationally restrain key pharmacophoric groups within the molecule. Comprehensive SAR was disclosed and the most promising compound 4x displayed superior activity both in BTK enzyme (IC50=4.8nM) and cellular inhibition (IC50=17nM) assays to that of RN486.
基于最近报道的临床前药物RN486的结构，设计了一系列新型可逆性BTK抑制剂。对RN486结合模式的了解促使设计新的抑制剂，这些抑制剂利用吡咯并[2,3-d]嘧啶来构象限制分子内的关键药效基团。公开了全面的构效关系，最有前景的化合物4x在BTK酶（IC50 = 4.8 nM）和细胞抑制（IC50 = 17 nM）试验中均显示出优于RN486的活性。
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