910235-65-3Relevant academic research and scientific papers
Discovery of potent and selective reversible Bruton's tyrosine kinase inhibitors
Qiu, Hui,Ali, Zahid,Bender, Andrew,Caldwell, Richard,Chen, Yi-Ying,Fang, Zhizhou,Gardberg, Anna,Glaser, Nina,Goettsche, Anja,Goutopoulos, Andreas,Grenningloh, Roland,Hanschke, Bettina,Head, Jared,Johnson, Theresa,Jones, Christopher,Jones, Reinaldo,Kulkarni, Shashank,Maurer, Christine,Morandi, Federica,Neagu, Constantin,Poetzsch, Sven,Potnick, Justin,Schmidt, Ralf,Roe, Katherine,Viacava Follis, Ariele,Wing, Carolyn,Zhu, Xiaohua,Sherer, Brian
, (2021)
Bruton's tyrosine kinase (BTK) is a cytoplasmic, non-receptor tyrosine kinase member of the TEC family of tyrosine kinases. Pre-clinical and clinical data have shown that targeting BTK can be used for the treatment for B-cell disorders. Here we disclose t
1,4,6-Trisubstituted imidazo[4,5-c]pyridines as inhibitors of Bruton's tyrosine kinase
Kraj?ovi?ová, Soňa,Jorda, Radek,Vanda, David,Soural, Miroslav,Kry?tof, Vladimír
, (2020/12/21)
Herein, we report an efficient synthetic approach towards trisubstituted imidazo [4,5-c]pyridines designed as inhibitors of Bruton's tyrosine kinase (BTK). Two alternative synthetic routes for the simple preparation of desired compounds with variable substitutions at the N1, C4, C6 positions were introduced with readily available building blocks. Further, the developed synthetic approach was feasible for isomeric compounds bearing imidazo [4,5-b]pyridine scaffolds. In contrast to expectations based on previous studies, the imidazo [4,5-c]pyridine inhibitor exhibited a significantly higher activity against BTK compared to its imidazo [4,5-b]pyridine isomer. An inherent SAR study in the series of imidazo [4,5-c]pyridine compounds revealed a remarkably high tolerance of C6 substitutions for both hydrophobic and hydrophilic substituents. Preliminary cellular experiments indicated selective BTK targeting in Burkitt lymphoma and mantle cell lymphoma cell lines. The inhibitors could thus serve as starting points for further development, eventually leading to BTK inhibitors that could be used after ibrutinib failure.
Pyrrolopyrimidine BTK inhibitor as well as preparation method and application thereof
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, (2021/11/03)
The invention provides a pyrrolopyrimidine BTK inhibitor as well as a preparation method and application thereof, and belongs to the technical field of biological medicines. The compound has the structural general formula shown in a formula (I). In-flight
NOVEL IRREVERSIBLE BRUTON'S TYROSINE KINASE INHIBITOR
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, (2019/01/04)
The present invention provides an inhibitor of Bruton's tyrosine kinase, which is a compound of formula (I), or its pharmaceutically acceptable salt, solvate, ester, acid, metabolite or prodrug. The present invention also provides a pharmaceutical composition comprsing the compound. The present invention also provides a method for inhibiting the activity of tyrosine kinase activity or for treating a disease, disorder, or condition, which would benefit from the inhibition of Bruton's tyrosine kinase(s), by using the Bruton's tyrosine kinase inhibitor, as well as application of the Bruton's tyrosine kinase inhibitor for the same.
PYRAZOLO[3,4-b]PYRIDINE AND PYRROLO[2,3-b]PYRIDINE INHIBITORS OF BRUTON'S TYROSINE KINASE
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Paragraph 0740-0741; 0764, (2018/07/31)
Disclosed are pyrazolo[3,4-b]pyridine and pyrrolo[2,3-b]pyridine inhibitors of Bruton's tyrosine kinase (Btk). Also disclosed are pharmaceutical compositions that include the compounds. Methods of using the Btk inhibitors are described, alone or in combin
Design and Synthesis of Novel Amino-triazine Analogues as Selective Bruton's Tyrosine Kinase Inhibitors for Treatment of Rheumatoid Arthritis
Kawahata, Wataru,Asami, Tokiko,Kiyoi, Takao,Irie, Takayuki,Taniguchi, Haruka,Asamitsu, Yuko,Inoue, Tomoko,Miyake, Takahiro,Sawa, Masaaki
, p. 8917 - 8933 (2018/10/09)
Bruton's tyrosine kinase (BTK) is a promising drug target for the treatment of multiple diseases, such as B-cell malignances, asthma, and rheumatoid arthritis. A series of novel aminotriazines were identified as highly selective inhibitors of BTK by a scaffold-hopping approach. Subsequent SAR studies of this series using two conformationally different BTK proteins, an activated form of BTK and an unactivated form of BTK, led to the discovery of a highly selective BTK inhibitor, 4b. With significant efficacy in models in vivo and good ADME and safety profiles, 4b was advanced into preclinical studies.
Design and synthesis of novel pyrimidine analogs as highly selective, non-covalent BTK inhibitors
Kawahata, Wataru,Asami, Tokiko,Irie, Takayuki,Sawa, Masaaki
, p. 145 - 151 (2017/12/06)
BTK is a promising target for the treatment of multiple diseases such as B cell malignances, asthma, and rheumatoid arthritis. Here, we report the discovery of a series of novel pyrimidine analogs as potent, highly selective, non-covalent inhibitors of BTK. Compound 25d demonstrated higher affinity to an unactivated conformation of BTK that resulted in an excellent kinase selectivity. Compound 25d showed a good oral bioavailability in mice, and significantly inhibits the PCA reaction in mice.
Discovery of N-(3-(5-((3-acrylamido-4-(morpholine-4-carbonyl)phenyl)amino)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2-methylphenyl)-4-(tert-butyl)benzamide (CHMFL-BTK-01) as a highly selective irreversible Bruton's tyrosine kinase (BTK) inhibitor
Liang, Qianmao,Chen, Yongfei,Yu, Kailin,Chen, Cheng,Zhang, Shouxiang,Wang, Aoli,Wang, Wei,Wu, Hong,Liu, Xiaochuan,Wang, Beilei,Wang, Li,Hu, Zhenquan,Wang, Wenchao,Ren, Tao,Zhang, Shanchun,Liu, Qingsong,Yun, Cai-Hong,Liu, Jing
, p. 107 - 125 (2017/03/21)
Currently there are several irreversible BTK inhibitors targeting Cys481 residue under preclinical or clinical development. However, most of these inhibitors also targeted other kinases such as BMX, JAK3, and EGFR that bear the highly similar active cysteine residues. Through a structure-based drug design approach, we discovered a highly potent (IC50: 7?nM) irreversible BTK inhibitor compound 9 (CHMFL-BTK-01), which displayed a high selectivity profile in KINOMEscan (S score (35)?=?0.00) among 468 kinases/mutants at the concentration of 1?μM. Compound 9 completely abolished BMX, JAK3 and EGFR's activity. Both X-ray crystal structure and cysteine-serine mutation mediated rescue experiment confirmed 9's irreversible binding mode. 9 also potently inhibited BTK Y223 auto-phosphorylation (EC50: 30?nM), arrested cell cycle in G0/G1 phase and induced apoptosis in U2932 and Pfeiffer cells. We believe these features would make 9 a good pharmacological tool to study the BTK related pathology.
HETEROARYL COMPOUNDS AS BTK INHIBITORS AND USES THEREOF
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Paragraph 0262, (2016/05/02)
The present invention relates to imidazo pyridine compounds, and pharmaceutically acceptable compositions thereof, useful as BTK inhibitors.
Structure-based drug design of RN486, a potent and selective Bruton's tyrosine kinase (BTK) inhibitor, for the treatment of rheumatoid arthritis
Lou, Yan,Han, Xiaochun,Kuglstatter, Andreas,Kondru, Rama K.,Sweeney, Zachary K.,Soth, Michael,McIntosh, Joel,Litman, Renee,Suh, Judy,Kocer, Buelent,Davis, Dana,Park, Jaehyeon,Frauchiger, Sandra,Dewdney, Nolan,Zecic, Hasim,Taygerly, Joshua P.,Sarma, Keshab,Hong, Junbae,Hill, Ronald J.,Gabriel, Tobias,Goldstein, David M.,Owens, Timothy D.
, p. 512 - 516 (2015/03/03)
Structure-based drug design was used to guide the optimization of a series of selective BTK inhibitors as potential treatments for Rheumatoid arthritis. Highlights include the introduction of a benzyl alcohol group and a fluorine substitution, each of which resulted in over 10-fold increase in activity. Concurrent optimization of drug-like properties led to compound 1 (RN486) (J. Pharmacol. Exp. Ther. 2012, 341, 90), which was selected for advanced preclinical characterization based on its favorable properties.
