- Design and synthesis of novel 1-substituted 3-(6-phenoxypyridin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine analogs as selective BTK inhibitors for the treatment of mantle cell lymphoma
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Ibrutinib (IBN), a first-in-class BTK-inhibitor, was approved by the FDA for the treatment of mantle cell lymphoma (MCL). Although IBN shows excellent performance as an anti-lymphoma agent, it has some undesirable side effects due to its off-target activities. Our studies yielded a novel series of 3-(6-phenoxypyridin-3-yl)-4-amine-1H-pyrazolo[3,4-d]pyrimidine derivatives capable of potent inhibition of Bruton's tyrosine kinase (BTK). Notably, compound 13e explained potent BTK inhibitory activity and could completely inhibit the phosphorylation of BTK and PLCγ2 in Z138 cells at low micromolar concentration. Compared with IBN, compound 13e improved anti-proliferative activities 3–40 folds in MCL cell lines with IC50 values lower than 1 μM. Low micromolar doses of 13e could induce strong cell apoptosis in Jeko-1 and Z138 cells. In addition, compound 13e showed greater BTK selectivity and higher stability in human liver microsomes than IBN and potential safety improvement for the treatment of MCL.
- Ran, Fansheng,Liu, Yang,Yu, Shengping,Guo, Kaiwen,Tang, Wendi,Chen, Xin,Zhao, Guisen
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- 1, 3-di-substituted-4-amino pyrazolopyrimidine compound, preparation method thereof and application of compound
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The invention relates to a 1, 3-di-substituted-4-amino pyrazolopyrimidine compound, a preparation method thereof and an application of the compound. The compound is provided with a structure as shownin a formula I. The invention further relates to a preparation method of the compound with the structure as shown in the formula I and a medicine composition. The invention further provides an application of the compound and pharmaceutically acceptable salt thereof to preparation of MCL (mantle cell lymphoma) resistance medicines.
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- CERTAIN CHEMICAL ENTITIES, COMPOSITIONS, AND METHODS
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Chemical entities that are kinase inhibitors, pharmaceutical compositions and methods of treatment of cancer are described.
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- BRUTON'S TYROSINE KINASE INHIBITORS
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Bruton's tyrosine kinase (Btk) inhibitors have the following Formula (I).
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Page/Page column 26
(2018/10/19)
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- SUBSTITUTED NICOTINIMIDE INHIBITORS OF BTK AND THEIR PREPARATION AND USE IN THE TREATMENT OF CANCER, INFLAMMATION AND AUTOIMMUNE DISEASE
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Compounds of Formula I, as shown below and defined herein: and pharmaceutically acceptable salts, syntheses, intermediates, formulations, and methods of treating diseases including cancer, inflammation, and autoimmune disease mediated at least in part by Bruton's Tyrosine Kinase (BTK).
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Page/Page column 66; 71
(2015/04/15)
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- Pyrazolopyrimidines as therapeutic agents
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The present invention is directed to pyrazolopyrimidine derivatives of formula (I) wherein the substituents are defined herein, which are useful as kinase inhibitors and as such are useful for affecting angiogenesis and diseases and conditions associated with angiogenesis.
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- Pyrazolopyrimidines as therapeutic agents
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The present invention provides compounds of Formula I, including pharmaceutically acceptable salts and/or prodrugs thereof, where G, R2, and R3 are defined as described herein.
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