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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, Yu1,2,3; Song, Peiran4,7; Song, Zilan2,3; Wang, Aoli5; Tong, Linjiang4; Geng, Meiyu4,6,7; Ding, Jian4,6,7; Liu, Qingsong5; Sun, Liping1; Xie, Hua4,6; Zhang, Ao2,3,6,7
2018-05-24
Source PublicationJOURNAL OF MEDICINAL CHEMISTRY
ISSN0022-2623
Volume61Issue:10Pages:4608-4627
Abstract

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.

DOI10.1021/acs.jmedchem.8b00441
WOS KeywordB-CELL MALIGNANCIES ; BTK INHIBITOR ; IRREVERSIBLE INHIBITORS ; ACALABRUTINIB ACP-196 ; RHEUMATOID-ARTHRITIS ; TEC FAMILY ; ACTIVATION ; LYMPHOMA ; POTENT ; PCI-32765
Indexed BySCI
Language英语
Funding ProjectPostgraduate Research & Practice Innovation Program of Jiangsu Province[KYCX17_0684] ; Jiangsu University Excellent Scientific and Technological Innovation Team ; Shanghai Commission of Science and Technology[14431900400] ; Shanghai Commission of Science and Technology[16XD1404600] ; Key Program of the Frontier Science of the Chinese Academy of Sciences[160621] ; International Cooperative Program[GJHZ1622] ; Chinese NSF[81703327] ; Chinese NSF[81773565] ; Chinese NSF[81430080] ; 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 ; Postgraduate Research & Practice Innovation Program of Jiangsu Province[KYCX17_0684]
WOS Research AreaPharmacology & Pharmacy
WOS SubjectChemistry, Medicinal
WOS IDWOS:000433403600022
PublisherAMER CHEMICAL SOC
Citation statistics
Cited Times:4[WOS]   [WOS Record]     [Related Records in WOS]
Document Type期刊论文
Identifierhttp://ir.hfcas.ac.cn:8080/handle/334002/36453
Collection中科院强磁场科学中心
Corresponding AuthorSun, Liping; Xie, Hua; Zhang, Ao
Affiliation1.China Pharmaceut Univ, Dept Med Chem, Nanjing 210009, Jiangsu, Peoples R China
2.Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, Shanghai 201203, Peoples R China
3.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
4.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Div Antitumor Pharmacol, Shanghai 201203, Peoples R China
5.Chinese Acad Sci, High Magnet Field Lab, Hefei 230031, Anhui, Peoples R China
6.Univ Chinese Acad Sci, Coll Pharm, Shanghai, Peoples R China
7.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 201210, Peoples R China
Recommended Citation
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.
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