Discovery of 4,7-Diamino-5-(4-phenoxyphenyl)-6-methylene-pyrinnido[5,4-b]pyrrolizines as Novel Bruton's Tyrosine Kinase Inhibitors

doi:10.1021/acs.jmedchem.8b00441

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	Discovery of 4,7-Diamino-5-(4-phenoxyphenyl)-6-methylene-pyrinnido[5,4-b]pyrrolizines as Novel Bruton's Tyrosine Kinase Inhibitors
	Xue, Yu 4,5,6; Song, Peiran 2,7; Song, Zilan 5,6; Wang, Aoli 1; Tong, Linjiang 7; Geng, Meiyu2,3,7 ; Ding, Jian2,3,7 ; Liu, Qingsong 1; Sun, Liping 4; Xie, Hua3,7
刊名	JOURNAL OF MEDICINAL CHEMISTRY
	2018-05-24
卷号	61 期号:10 页码:4608-4627
ISSN号	0022-2623
DOI	10.1021/acs.jmedchem.8b00441
文献子类	Article
英文摘要	An alternative medicinal chemistry approach was conducted on Bruton's tyrosine kinase (BTK) inhibitor 1 (ibrutinib) by merging the pyrazolo[3,4-d]pyrimidine component into a tricyclic skeleton. Two types of compounds were prepared, and their biochemical activities on BTK as well as stereochemistry effects were determined. Structural optimization focusing on the reactive binding group to BTK Cys481 and on the metabolic site guided by metabolic study were conducted. 7S was identified as the most potent showing an IC50 value of 0.4 nM against BTK and 16 nM against BTK-dependent TMD8 cells. Compared to 1, 7S was slightly more selective with strong inhibition on the B-cell receptor signaling pathway. In a TMD8 cell derived animal xenograft model, 7S showed a relative tumor volume of 5.3 at 15 mg/kg QD dosage that was more efficacious than 1 (RTV 6.6) at a higher dose of 25 mg/kg QD. All these results suggest 7S as a new BTK inhibitor worthy of further profiling.
资助项目	Chinese NSF[81430080] ; Chinese NSF[81773565] ; Chinese NSF[81703327] ; International Cooperative Program[GJHZ1622] ; Key Program of the Frontier Science of the Chinese Academy of Sciences[160621] ; Shanghai Commission of Science and Technology[16XD1404600] ; Shanghai Commission of Science and Technology[14431900400] ; Jiangsu University Excellent Scientific and Technological Innovation Team[00000000] ; Postgraduate Research & Practice Innovation Program of Jiangsu Province[KYCX17_0684]
WOS关键词	B-CELL MALIGNANCIES ; BTK INHIBITOR ; IRREVERSIBLE INHIBITORS ; ACALABRUTINIB ACP-196 ; RHEUMATOID-ARTHRITIS ; TEC FAMILY ; ACTIVATION ; LYMPHOMA ; POTENT ; PCI-32765
WOS研究方向	Pharmacology & Pharmacy
语种	英语
出版者	AMER CHEMICAL SOC
WOS记录号	WOS:000433403600022
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/279748]
专题	药理学第一研究室中科院受体结构与功能重点实验室新药研究国家重点实验室药物化学研究室
通讯作者	Sun, Liping; Xie, Hua; Zhang, Ao
作者单位	1.Chinese Acad Sci, High Magnet Field Lab, Hefei 230031, Anhui, Peoples R China; 2.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 201210, Peoples R China 3.Univ Chinese Acad Sci, Coll Pharm, Shanghai, Peoples R China; 4.China Pharmaceut Univ, Dept Med Chem, Nanjing 210009, Jiangsu, Peoples R China; 5.Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, Shanghai 201203, Peoples R China; 6.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China; 7.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Div Antitumor Pharmacol, Shanghai 201203, Peoples R China;
推荐引用方式 GB/T 7714	Xue, Yu,Song, Peiran,Song, Zilan,et al. Discovery of 4,7-Diamino-5-(4-phenoxyphenyl)-6-methylene-pyrinnido[5,4-b]pyrrolizines as Novel Bruton's Tyrosine Kinase Inhibitors[J]. JOURNAL OF MEDICINAL CHEMISTRY,2018,61(10):4608-4627.
APA	Xue, Yu.,Song, Peiran.,Song, Zilan.,Wang, Aoli.,Tong, Linjiang.,...&Zhang, Ao.(2018).Discovery of 4,7-Diamino-5-(4-phenoxyphenyl)-6-methylene-pyrinnido[5,4-b]pyrrolizines as Novel Bruton's Tyrosine Kinase Inhibitors.JOURNAL OF MEDICINAL CHEMISTRY,61(10),4608-4627.
MLA	Xue, Yu,et al."Discovery of 4,7-Diamino-5-(4-phenoxyphenyl)-6-methylene-pyrinnido[5,4-b]pyrrolizines as Novel Bruton's Tyrosine Kinase Inhibitors".JOURNAL OF MEDICINAL CHEMISTRY 61.10(2018):4608-4627.