- Synthesis and biological evaluation of 6-(pyrimidin-4-yl)-1H-pyrazolo[4,3-b]pyridine derivatives as novel dual FLT3/CDK4 inhibitors
-
FMS-like tyrosine kinase-3 (FLT3) and cyclin-dependent kinase 4/6 (CDK4/6) inhibitors have been proven to play a significant role in tumor therapy. Herein, based on the previously reported JAK2/FLT3 inhibitor 18e, we described the synthesis, structure–activity relationship and biological evaluation of a series of unique 6-(pyrimidin-4-yl)-1H-pyrazolo[4,3-b]pyridine derivatives that inhibited FLT3 and CDK4 kinases. The optimized compound 23k exhibited low nanomolar range activities with IC50 values of 11 and 7 nM for FLT3 and CDK4, respectively. In the MV4-11 xenograft tumor model, the tumor growth inhibition rate of 23k dosed at 200 mg/kg was 67%, suggesting that 23k possessed an antitumor therapeutic effect.
- Chen, Lijuan,Chen, Yong,Deng, Dexin,Fu, Suhong,Guo, Yong,Hu, Mengshi,Li, Xiandeng,Liu, Kongjun,Peng, Bin,Si, Wenting,Tan, Yan,Tang, Minghai,Wang, Huan,Yang, Tao,Yang, Yingxue,Yang, Zhuang,Zhang, Chufeng
-
-
- CDK4/6 INHIBITORS AND USE THEREOF
-
The present disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt, a solvate, a stereoisomer, or tautomer thereof, a pharmaceutical composition comprising a compound of formula (A) or formula (B), and any subgenera thereof, and use of said compounds and compositions thereof, wherein R1, R2, R3a, R3b, R5, R6, X1, X2, Y and n are described herein.
- -
-
Paragraph 616; 621; 622
(2019/03/05)
-
- Design and synthesis of 4-(2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)-N-(5-(piperazin-1-ylmethyl)pyridine-2-yl)pyrimidin-2-amine as a highly potent and selective cyclin-dependent kinases 4 and 6 inhibitors and the discovery of structure-activity relationships
-
Cyclin-dependent kinases 4/6 play an important role in regulation of cell cycle, and overexpress in a variety of cancers. Up to now, new CDK inhibitors still need to be developed due to its poor selectivity. Herein we report a novel series of 4-(2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole-7-yl)-N-(5-(piperazin-1-ylmethyl)pyridine-2-yl)pyrimidin-2-amine anologues as potent CDK 4/6 inhibitors based on LY2835219 (Abemaciclib). Compound 10d, which exhibits approximate potency on CDK4/6 (IC50 = 7.4/0.9 nM), has both good pharmacokinetic characters and high selectivity on CDK1 compared with LY2835219. Overall, compound 10d could be a promising candidate and a good starting point as anticancer drugs.
- Wang, Yan,Liu, Wen-Jian,Yin, Lei,Li, Heng,Chen, Zhen-Hua,Zhu, Dian-Xi,Song, Xiu-Qing,Cheng, Zhen-Zhen,Song, Peng,Wang, Zhan,Li, Zhi-Gang
-
supporting information
p. 974 - 978
(2018/02/13)
-
- A highly potent CDK4/6 inhibitor was rationally designed to overcome blood brain barrier in gliobastoma therapy
-
Glioblastoma multiforme (GBM) is the most common and deadliest of malignant brain tumors in adults. Disease development is associated with dysregulation of the cyclin D-CDK4/6-INK4-Rb pathway, resulting in increased proliferation; thus, CDK4/6 kinase inhibitors are promising candidates for GBM treatment. The recently developed CDK4/6 inhibitors, palbociclib, ribociclib, and abemaciclib, are effective in subcutaneous glioma models, but their blood-brain barrier (BBB) permeability is poor, limiting drug delivery to the central nervous system. Here, we designed and synthesized a series of novel CDK4/6 inhibitors with favorable BBB permeability for the treatment of GBM. Compound 11 exhibited a favorable pharmacological profile and significant penetration of the BBB with the Kp value of 4.10 and the Kp,uu value of 0.23 in mice after an oral dose of 10 mg/kg. IC50 values for CDK4/cyclin D1 and CDK6/cyclin D3 were 3 nM and 1 nM, respectively. In vivo studies with an orthotopic xenograft mouse model of GBM showed that 11 had tumor growth inhibition values ranging from 62% to 99% for doses ranging from 3.125 to 50 mg/kg, and no significant body weight loss was observed. The increase in life span based on the median survival time of vehicle-treated animals in mice administered a dose of 50 mg/kg was significant at 162% (p 0.0001). These results suggest that compound 11 is a promising candidate for further investigation as an effective drug for the treatment of GBM.
- Yin, Lei,Li, Heng,Liu, Wenjian,Yao, Zhenglin,Cheng, Zhenzhen,Zhang, Huabei,Zou, Hui
-
-
- PROTEIN KINASE INHIBITOR, PREPARATION METHOD AND MEDICAL USE THEREOF
-
The present invention provides compounds as shown in formula I or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, a deuterated compound, a prodrug or a mixture thereof, or a pharmaceutically acceptable salt or solvate of the compounds as shown in formula I or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, a deuterated compound, a prodrug or a mixture thereof, wherein R1 to R7 are as defined in the description. The present invention also provides a preparation method and a medical use of the compounds, The compounds of the present invention have an activity superior or equivalent to the candidate drug LY283521 9 currently under phase III clinical trial, and some of the compounds exhibit better selectivity. Moreover, the preferred compounds exhibit good absorption and good blood-brain distribution when administered orally. The compounds of the present invention thus show promise for development into novel drugs for the treatment of diseases associated with cell proliferation, particularly brain tumors, providing new options for clinicians and patients.
- -
-
Paragraph 0097; 0098; 0099; 0100
(2018/10/27)
-
- Protein kinase inhibitor and its preparation method and medical application
-
The invention provides a compound shown in the structural formula I or its tautomer, mesomer, racemate, enantiomer, diastereoisomer or their mixture, or a pharmaceutically acceptable salt or solvate of the compound shown in the structural formula I or its tautomer, mesomer, racemate, enantiomer, diastereoisomer or their mixture. The ring A, R1, R2, R3 and R4 are defined in the specification. The invention also provides a preparation method of the compound shown in the structural formula I and a use of the compound in preparation of a drug for treating cell proliferative disorder.
- -
-
Paragraph 0142-0145
(2017/05/26)
-
- Highly Potent, Selective, and Orally Bioavailable 4-Thiazol-N-(pyridin-2-yl)pyrimidin-2-amine Cyclin-Dependent Kinases 4 and 6 Inhibitors as Anticancer Drug Candidates: Design, Synthesis, and Evaluation
-
Cyclin D dependent kinases (CDK4 and CDK6) regulate entry into S phase of the cell cycle and are validated targets for anticancer drug discovery. Herein we detail the discovery of a novel series of 4-thiazol-N-(pyridin-2-yl)pyrimidin-2-amine derivatives as highly potent and selective inhibitors of CDK4 and CDK6. Medicinal chemistry optimization resulted in 83, an orally bioavailable inhibitor molecule with remarkable selectivity. Repeated oral administration of 83 caused marked inhibition of tumor growth in MV4-11 acute myeloid leukemia mouse xenografts without having a negative effect on body weight and showing any sign of clinical toxicity. The data merit 83 as a clinical development candidate.
- Tadesse, Solomon,Yu, Mingfeng,Mekonnen, Laychiluh B.,Lam, Frankie,Islam, Saiful,Tomusange, Khamis,Rahaman, Muhammed H.,Noll, Benjamin,Basnet, Sunita K. C.,Teo, Theodosia,Albrecht, Hugo,Milne, Robert,Wang, Shudong
-
p. 1892 - 1915
(2017/03/17)
-
- Deuterium-modified Abemaciclib derivative
-
The invention belongs to the field of medicinal chemistry and specifically relates to a deuterium-modified Abemaciclib derivative, a preparation method of the derivative, a pharmaceutical composition containing the deuterium-modified Abemaciclib derivative, and application of the deuterium-modified Abemaciclib derivative and the pharmaceutical composition in the preparation of a medicine for treating cell proliferative diseases. In comparison with Abemaciclib, some compounds of the invention (especially compounds in the embodiment) have more excellent pharmacokinetic properties. It is expected that clinical dosage will be reduced. Thus, treatment cost is reduced so as to benefit more patients.
- -
-
Paragraph 0107; 0108; 0109; 0110; 0111; 0112
(2017/08/02)
-
- Development of a Leuckart-Wallach Reaction in Flow for the Synthesis of Abemaciclib
-
The development of a route for a key building block in the synthesis of abemaciclib is described. The route proceeds through a Leuckart-Wallach reductive amination in flow followed by an Ullmann amination with aqueous ammonia. Key to the Leuckart-Wallach reductive amination was the addition of trimethyl orthoformate for water removal, running the reaction continuously in a pipes-in-series reactor for rapid heat-up, and building a kinetic model to understand time and temperature parameters for the feed tank storage. The product of the Leuckart-Wallach reductive amination is forward processed in batch and telescoped with the Ullmann amination and subsequent workup. The development resulted in a robust process that has successfully been run on the production scale.
- Frederick, Michael O.,Pietz, Mark A.,Kjell, Douglas P.,Richey, Rachel N.,Tharp, Gregg A.,Touge, Taichiro,Yokoyama, Naota,Kida, Michio,Matsuo, Toshiyasu
-
supporting information
p. 1447 - 1451
(2017/09/22)
-
- Substituted benzimidazole derivatives
-
The invention belongs to the field of pharmaceutical chemistry, particularly relates to substituted benzimidazole derivatives as well as a preparation method and pharmaceutical composition thereof and further relates to an application of the substituted b
- -
-
Paragraph 0164; 0165; 0166
(2018/01/09)
-
- Pyrimidine or pyridine pyridine ketone compound and its preparation method and application (by machine translation)
-
The invention discloses a kind of type I of the pyrimidine or pyridine pyridine ketone compound and its preparation and application, which belongs to the technical field of pharmaceutical preparation. The compounds have high-efficient and selectively inhibit the cell cycle dependent kinases (Cdks) CDK4 and CDK6 active, and then by inhibiting CDK4/CDK6 prevent tumor cell division. Therefore, the compounds of this invention can be used for CDK4 and CDK6 the involved in cell cycle control disorders result in various diseases, especially suitable for the treatment of malignant tumors. (by machine translation)
- -
-
Paragraph 0220
(2016/10/09)
-
- 2-H-INDAZOLE DERIVATIVES AS CYCLIN-DEPENDENT KINASE (CDK) INHIBITORS AND THERAPEUTIC USES THEREOF
-
Indazole compounds of formula (I) as cyclin-dependent kinase (CDK) and cellproliferation inhibitors, and therapeutic uses and methods of preparation thereof, are disclosed. These compounds, and pharmaceutically acceptable salts, solvates, prodrugs, and pharmaceutical compositions thereof, are useful for treating diseases and disorders associated with activity of cyclin-dependent kinases, in particular CDK4/6, including but not limited to various cancers and inflammation-related diseases or conditions:
- -
-
Page/Page column 21; 23; 24
(2016/02/12)
-
- COMBINATION THERAPY FOR CANCER
-
The present invention provides preparation of medicaments for use in treating and methods of treating non-small cell lung cancer in a patient comprising: [5-(4-ethyl-piperazin-1-ylmethyl)-pyridin-2-yl]-[5-fluoro-4-(7-fluoro-3-isopropyl-2-methyl-3H- benzoimidazol-5-yl)-pyrimidin-2-yl]-amine, or a pharmaceutically acceptable salt thereof, in combination, as further described herein, with an anti-VEGFR2 antibody, preferably, ramucirumab.
- -
-
Page/Page column 20-21
(2015/09/28)
-
- PROTEIN KINASE INHIBITORS
-
The present invention provides a compound of formula (I): or a pharmaceutically acceptable salt thereof which is useful in the treatment of cell proliferative diseases.
- -
-
Page/Page column 9
(2010/07/04)
-