82040-90-2Relevant academic research and scientific papers
JAK3 inhibitors based on thieno[3,2-d]pyrimidine scaffold: design, synthesis and bioactivity evaluation for the treatment of B-cell lymphoma
Chi, Fuyun,Chen, Lixue,Wang, Changyuan,Li, Lei,Sun, Xiuli,Xu, Youjun,Ma, Tengyue,Liu, Kexin,Ma, Xiaodong,Shu, Xiaohong
, (2020/01/08)
JAK3 is predominantly expressed in hematopoietic cells and has been a promising therapeutic target for the treatment of B-cell lymphoma. In this study, a new class of thieno[3,2-d]pyrimidines harboring acrylamide pharmacophore were synthesized as potent covalent JAK3 inhibitors (IC50 50 values of 1.9 nM and 1.8 nM, respectively. Furthermore, compared with the reference agents, Spebrutinib and Ibrutinib, 9a not only demonstrated enhanced antiproliferative activity against B lymphoma cells, but also showed very weak proliferative inhibition against normal peripheral blood mononuclear cells (PBMCs) at a concentration of 20 μM. Analysis of the mechanism revealed that 9a could induce the obvious apoptosis in B lymphoma cells and prevent JAK3-STAT3 cascade as well as BTK pathway. Taken together, 9a may be served as a potential new JAK3 inhibitor for the treatment of B-cell lymphoma.
Identification of highly potent BTK and JAK3 dual inhibitors with improved activity for the treatment of B-cell lymphoma
Ge, Yang,Wang, Changyuan,Song, Shijie,Huang, Jiaxin,Liu, Zhihao,Li, Yongming,Meng, Qiang,Zhang, Jianbin,Yao, Jihong,Liu, Kexin,Ma, Xiaodong,Sun, Xiuli
, p. 1847 - 1857 (2017/12/04)
The BTK and JAK3 receptor tyrosine kinases are two validated and therapeutically amenable targets in the treatment of B-cell lymphomas. Here we report the identification of several classes of pyrimidine derivatives as potent BTK and JAK3 dual inhibitors.
Structure-based design of novel 2-amino-6-phenyl-pyrimido[5′, 4′:5,6]pyrimido[1,2-a]benzimidazol-5(6H)-ones as potent and orally active inhibitors of lymphocyte specific kinase (Lck): Synthesis, SAR, and in vivo anti-inflammatory activity
Martin, Matthew W.,Newcomb, John,Nunes, Joseph J.,Boucher, Christina,Chai, Lilly,Epstein, Linda F.,Faust, Theodore,Flores, Sylvia,Gallant, Paul,Gore, Anu,Gu, Yan,Hsieh, Faye,Huang, Xin,Kim, Joseph L.,Middleton, Scot,Morgenstern, Kurt,Oliveira-dos-Santos, Antonio,Patel, Vinod F.,Powers, David,Rose, Paul,Tudor, Yanyan,Turci, Susan M.,Welcher, Andrew A.,Zack, Debra,Zhao, Huilin,Zhu, Li,Zhu, Xiaotian,Ghiron, Chiara,Ermann, Monika,Johnston, David,Saluste, Carl-Gustaf Pierre
, p. 1637 - 1648 (2008/12/22)
Lck, or lymphocyte specific kinase, is a cytoplasmic tyrosine kinase of the Src family expressed in T-cells and NK cells. Genetic evidence from knockout mice and human mutations demonstrates that Lck kinase activity is critical for T-cell receptor-mediated signaling, leading to normal T-cell development and activation. A small molecule inhibitor of Lck is expected to be useful in the treatment of T-cell-mediated autoimmune and inflammatory disorders and/or organ transplant rejection. In this paper, we describe the structure-guided design, synthesis, structure-activity relationships, and pharmacological characterization of 2-amino-6-phenylpyrimido[5′,4′:5,6]pyrimido[1,2- a]benzimidazol-5(6H)-ones, a new class of compounds that are potent inhibitors of Lck. The most promising compound of this series, 6-(2,6-dimethylphenyl)-2- ((4-(4-methyl-1-piperazinyl)phenyl)amino)pyrimido[5′,4′:5,6] pyrimido-[1,2-a]benzimidazol-5(6H)-one (25), exhibits potent inhibition of Lck kinase activity. This activity translates into inhibition of in vitro cell-based assays and in vivo models of T-cell activation and arthritis, respectively.
Novel 2-aminopyrimidine carbamates as potent and orally active inhibitors of Lck: Synthesis, SAR, and in vivo antiinflammatory activity
Martin, Matthew W.,Newcomb, John,Nunes, Joseph J.,McGowan, David C.,Armistead, David M.,Boucher, Christina,Buchanan, John L.,Buckner, William,Chai, Lilly,Elbaum, Daniel,Epstein, Linda F.,Faust, Theodore,Flynn, Shaun,Gallant, Paul,Gore, Anu,Gu, Yan,Hsieh, Faye,Huang, Xin,Lee, Josie H.,Metz, Daniela,Middleton, Scot,Mohn, Deanna,Morgenstern, Kurt,Morrison, Michael J.,Novak, Perry M.,Oliveira-Dos-Santos, Antonio,Powers, David,Rose, Paul,Schneider, Stephen,Sell, Stephanie,Tudor, Yanyan,Turci, Susan M.,Welcher, Andrew A.,White, Ryan D.,Zack, Debra,Zhao, Huilin,Zhu, Li,Zhu, Xiaotian,Ghiron, Chiara,Amouzegh, Patricia,Ermann, Monika,Jenkins, James,Johnston, David,Napier, Spencer,Power, Eoin
, p. 4981 - 4991 (2007/10/03)
The lymphocyte-specific kinase (Lck) is a cytoplasmic tyrosine kinase of the Src family expressed in T cells and NK cells. Genetic evidence in both mice and humans demonstrates that Lck kinase activity is critical for signaling mediated by the T cell receptor (TCR), which leads to normal T cell development and activation. A small molecule inhibitor of Lck is expected to be useful in the treatment of T cell-mediated autoimmune and inflammatory disorders and/or organ transplant rejection. In this paper, we describe the synthesis, structure-activity relationships, and pharmacological characterization of 2-aminopyrimidine carbamates, a new class of compounds with potent and selective inhibition of Lck. The most promising compound of this series, 2,6-dimethylphenyl 2-((3,5-bis(methyloxy)-4-((3-(4-methyl-1-piperazinyl)propyl)- oxy)phenyl)amino)-4-pyrimidinyl(2,4-bis(methyloxy)phenyl)carbamate (43) exhibits good activity when evaluated in in vitro assays and in an in vivo model of T cell activation.
Photoinduced Intramolecular Substitution. II. Absence of meta-Favoring Effect in Nucleophilic Photosubstitution of Nitroveratrole Derivatives
Mutai, Kiyoshi,Yokoyama, Kenji,Kanno, Sei-ichiro,Kobayashi, Keiji
, p. 1112 - 1115 (2007/10/02)
Possible occurrence of the photo-Smiles rearrangement accompanying meta-favoring nucleophilic aromatic substitution was examined in a homologous series of 1-(2-methoxy-4-nitrophenoxy)-ω-anilinoalkanes.The structure of reaction products, the reaction kinet
