European Journal of Medicinal Chemistry p. 96 - 112 (2018)
Update date:2022-08-17
Topics:
He, Linhong
Pei, Heying
Zhang, Chufeng
Shao, Mingfeng
Li, Dan
Tang, Mingli
Wang, Taijing
Chen, Xiaoxin
Xiang, Mingli
Chen, Lijuan
Bruton's tyrosine kinase (Btk) is a Tec family kinase with a well-defined role in the B cell receptor (BCR) and Fcγ receptor (FcR) signaling pathways, which makes it a uniquely attractive target for the treatment of autoimmune diseases, such as rheumatoid arthritis (RA). We reported a series of compounds bearing 7H-pyrrolo [2,3-d]pyrimidin-4-amine scaffold that potently inhibited Btk in vitro. Analysis of the structure-activity relationships (SAR) and drug-like profiles led to the discovery of the optimal compound B16. B16 preferentially inhibited Btk (IC50 = 21.70 ± 0.82 nM) over closely related kinases with moderate selectivity. Cell-based tests also confirmed that B16 significantly inhibited Btk Y223 auto-phosphorylation and PLCγ2 Y1217 phosphorylation. MTT revealed that B16 displayed weak suppression against normal LO2, HEK293 and THP-1 cell lines with IC50 values over 30 μM. Moreover, B16 showed very weak potential to block the hERG channel (IC50 = 11.10 μM) in comparison to ibrutinib (IC50 = 0.97 μM). Owing to its favorable physicochemical properties (ClogP = 2.53, aqueous solubility ≈ 0.1 mg/mL), pharmacokinetic profiles (F = 49.15%, t1/2 = 7.02 h) and reasonable CYP450 profile, B16 exhibited potent anti-arthritis activity and similar efficacy to ibrutinib in reducing paw thickness in CIA mice. In conclusion, B16 is a potent, selective and durable inhibitor of Btk and has the potential to a safe and efficacious treatment for arthritis.
View Morewebsite:http://www.greenutra.cn
Contact:0086-411-39553357
Address:No. 7-1-1802, Huizhi Garden,Ocean Square,Dalian, 116033, China
Contact:+86-633-8332928
Address:No.1,Huanghai Yilu.Rizhao,Shandong
Nanjing Chemlin Chemical Co., Ltd.
website:http://www.echemlin.cn
Contact:+86-25-83697070
Address:Rm.902 Longyin Plaza, No. 217 Zhongshan Rd.(N) Nanjing 210009,China
Beijing Tianjia Chemical Science & Technology Co.,Ltd
Contact:86-0550-2392698
Address:No.388, Shiliang Road (East),
Beijing Greenchem Technology Co.,Ltd. ( Panjin Greenchem Technology Co.Ltd .)
website:http://www.bjgreenchem.com/
Contact:+86-427-6515887
Address:301,302, 3rd Floor, Building C-7, Dongsheng Science Park, Northern Territory, Zhongguancun, No. 66, Xixiaokou Road, Haidian District, Beijing
Doi:10.1002/ejoc.201701234
(2017)Doi:10.1002/hlca.19960790125
(1996)Doi:10.1021/acs.orglett.8b00831
(2018)Doi:10.1016/S0968-0896(02)00068-8
(2002)Doi:10.1016/j.tetlet.2011.01.126
(2011)Doi:10.1016/S0957-4166(97)00156-0
(1997)