Pyrrolo[2,3-b]pyridine derivatives as potent Bruton's tyrosine kinase inhibitors

被引：20

作者：

Zhao, Xinge ^{[1
,2
]}

Huang, Wei ^{[2
]}

Wang, Yazhou ^{[2
]}

Xin, Minhang ^{[3
]}

Jin, Qiu ^{[2
]}

Cai, Jianfeng ^{[2
]}

Tang, Feng ^{[2
]}

Zhao, Yong ^{[2
]}

Xiang, Hua ^{[1
]}

机构：

[1] China Pharmaceut Univ, Sch Pharm, Dept Med Chem, Nanjing 210009, Jiangsu, Peoples R China

[2] Jiangsu Simcere Pharmaceut Co Ltd, Jiangsu Key Lab Mol Targeted Antitumor Drug Res, Nanjing 210042, Jiangsu, Peoples R China

[3] Xi An Jiao Tong Univ, Hlth Sci Ctr, Sch Pharm, Dept Med Chem, Xian 710061, Peoples R China

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2015年 / 23卷 / 15期

关键词：

BTK kinase; Inhibitor; Pyrrolo[2,3-b]pyridine; SAR; X-LINKED AGAMMAGLOBULINEMIA; CYTOCHROME BC(1) COMPLEX; B-CELL MALIGNANCIES; INFLAMMATORY DISEASES; BIOLOGICAL EVALUATION; RHEUMATOID-ARTHRITIS; BTK INHIBITORS; DISCOVERY; SCAFFOLD; DESIGN;

D O I：

10.1016/j.bmc.2015.06.023

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

A series of pyrrolo[2,3-b]pyridine-based derivatives were designed as potent Bruton's tyrosine kinase (BTK) inhibitors by using a scaffold-hopping strategy. Structure-activity relationship studies identified five compounds (3n, 3p, 3q, 3r, and 3s) with IC50 of less than 10 nM in BTK enzyme assay and five compounds (3m, 3n, 3o, 3p, and 3t) with IC50 of less than 20 nM in Ramos cell assay. As one of the most potent inhibitors, compound 3p exhibited superior activity to that of compound 1 (RN486) and pyrrolo[ 2,3-d]pyrimidine derivative 2 in both BTK enzymatic (IC50 = 6.0 nM) and cellular inhibition (IC50 = 14 nM) assays. In addition, 3p displayed favorable overall pharmacokinetic profiles compared with 1 and 2. (C) 2015 Elsevier Ltd. All rights reserved.

引用

页码：4344 / 4353

页数：10

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