30069-31-9Relevant academic research and scientific papers
Evaluation of carbon-11 labeled 5-(1-methyl-1H-pyrazol-4-yl)-N-(2-methyl-5-(3-(trifluoromethyl)benzamido)phenyl)nicotinamide as PET tracer for imaging of CSF-1R expression in the brain
Chin, Frederick T.,Kooijman, Esther J. M.,Nezam, Madina,Reyes, Samantha T.,Shen, Bin,Windhorst, Albert D.,van der Wildt, Berend
, (2021/06/15)
Pharmacological targeting of tumor associated macrophages and microglia in the tumor microenvironment is a novel therapeutic strategy in the treatment of glioblastoma multiforme. As such, the colony stimulating factor-1 receptor (CSF-1R) has been identified as a druggable target. However, no validated companion diagnostic marker for these therapies exists to date. Towards development of a CSF-1R PET tracer, a set of six compounds based on recently reported CSF-1R inhibitor 5-(1-methyl-1H-pyrazol-4-yl)-N-(2-methyl-5-(3-(trifluoromethyl)benzamido)phenyl)nicotinamide (Compound 5) was designed, synthesized and evaluated in vitro for potency and selectivity. The highest affinity for CSF-1R was found for compound 5 (IC50: 2.7 nM). Subsequent radiosynthesis of [11C]5 was achieved in 2.0 ± 0.2% yield (decay corrected to start of synthesis) by carbon-11 carbon monoxide aminocarbonylation in 40 min after end of bombardment. In vitro autoradiography with [11C]5 on rat brain sections demonstrated high specific binding, but also strong off-target binding. Ex vivo, only intact tracer was observed in blood plasma at 90 min post injection in healthy rats. PET scanning results demonstrated negligible brain uptake under baseline conditions and this brain uptake did not increase by blocking of efflux transporters using Tariquidar. To conclude, [11C]5 was successfully synthesized and evaluated in healthy rats. However, the inability of [11C]5 to cross the blood-brain-barrier excludes its use for imaging of CSF-1R expression in the brain.
Discovery and Identification of Small Molecules as Methuosis Inducers with in Vivo Antitumor Activities
Huang, Wei,Sun, Xihuan,Li, Yunzhan,He, Zhixiang,Li, Li,Deng, Zhou,Huang, Xiaoxing,Han, Shang,Zhang, Ting,Zhong, Jiaji,Wang, Zheng,Xu, Qingyan,Zhang, Jianming,Deng, Xianming
, p. 5424 - 5434 (2018/06/18)
Methuosis is a novel nonapoptotic mode of cell death characterized by vacuole accumulation in the cytoplasm. In this article, we describe a series of azaindole-based compounds that cause vacuolization in MDA-MB-231 cells. The most potent vacuole inducer,
DUAL SRC/P38 KINASE INHIBITOR COMPOUNDS AND THEIR USE AS THERAPEUTIC AGENTS
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, (2017/06/12)
Dual Src/p38 kinase inhibitor compounds and compositions comprising the same are disclosed. Methods of using the compounds in the treatment of hyperproliferative disease such as cancer are also disclosed.
Discovery of 2-((3-Amino-4-methylphenyl)amino)-N-(2-methyl-5-(3-(trifluoromethyl)benzamido)phenyl)-4-(methylamino)pyrimidine-5-carboxamide (CHMFL-ABL-053) as a Potent, Selective, and Orally Available BCR-ABL/SRC/p38 Kinase Inhibitor for Chronic Myeloid Leukemia
Liang, Xiaofei,Liu, Xiaochuan,Wang, Beilei,Zou, Fengming,Wang, Aoli,Qi, Shuang,Chen, Cheng,Zhao, Zheng,Wang, Wenchao,Qi, Ziping,Lv, Fengchao,Hu, Zhenquan,Wang, Li,Zhang, Shanchun,Liu, Qingsong,Liu, Jing
, p. 1984 - 2004 (2016/03/22)
Starting from a dihydropyrimidopyrimidine core scaffold based compound 27 (GNF-7), we discovered a highly potent (ABL1: IC50 of 70 nM) and selective (S score (1) = 0.02) BCR-ABL inhibitor 18a (CHMFL-ABL-053). Compound 18a did not exhibit apparent inhibitory activity against c-KIT kinase, which is the common target of currently clinically used BCR-ABL inhibitors. Through significant suppression of the BCR-ABL autophosphorylation (EC50 about 100 nM) and downstream mediators such as STAT5, Crkl, and ERK's phosphorylation, 18a inhibited the proliferation of CML cell lines K562 (GI50 = 14 nM), KU812 (GI50 = 25 nM), and MEG-01 (GI50 = 16 nM). A pharmacokinetic study revealed that 18a had over 4 h of half-life and 24% bioavailability in rats. A 50 mg/kg/day dosage treatment could almost completely suppress tumor progression in the K562 cells inoculated xenograft mouse model. As a potential useful drug candidate for CML, 18a is under extensive preclinical safety evaluation now.
ISOQUINOLINE-5-CARBOXAMIDE DERIVATIVE HAVING INHIBITORY ACTIVITY FOR PROTEIN KINASE
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, (2015/06/03)
A compound selected from the group consisting of an isoquinoline-5-carboxamide derivative of formula (I), a pharmaceutically acceptable salt, an isomer, a hydrate and a solvate thereof is effective for the prevention or treatment of diseases associated with abnormal cell growth, which are caused by abnormal activation of a protein kinases.
ISOQUINOLINE-5-CARBOXAMIDE DERIVATIVE HAVING INHIBITORY ACTIVITY FOR PROTEIN KINASE
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, (2015/07/15)
A compound selected from the group consisting of an isoquinoline-5-carboxamide derivative of formula (I), a pharmaceutically acceptable salt, an isomer, a hydrate and a solvate thereof is effective for the prevention or treatment of diseases associated with abnormal cell growth, which are caused by abnormal activation of a protein kinases.
Design, synthesis and biological evaluation of bis-aryl ureas and amides based on 2-amino-3-purinylpyridine scaffold as DFG-out B-Raf kinase inhibitors
Yang, Weimin,Chen, Yadong,Zhou, Xiang,Gu, Yazhou,Qian, Wenqi,Zhang, Fan,Han, Wei,Lu, Tao,Tang, Weifang
, p. 581 - 596 (2014/12/12)
By combining the scaffolds of UI-125 and Sorafenib, a series of bis-aryl ureas and amides based on 2-amino-3-purinylpyridine moiety were designed and synthesized as novel DFG-out B-RafV600E inhibitors. Among them, 20c-e, 20g and 21h displayed potent antiproliferative activities against melanoma A375 (B-RafV600E) cell lines with IC50 values of 3.190, 2.276, 1.856, 1.632 μM and 1.839 μM, respectively, comparable with the positive control Vemurafenib (IC50 Combining double low line 3.32 μM). Selected compounds were tested for the ERK inhibition in human melanoma A375 (B-RafV600E) and SK-MEL-2 (B-RafWT) cell lines by Western blot. The results revealed that our compounds inhibited the proliferation of melanoma A375 cells (B-RafV600E) through ERK pathway, without paradoxical activation of ERK in melanoma SK-MEL-2 cells (B-RafWT). Eventually, 20g and 21h were selected to confirm their inhibitory effects on tumor growth in A375 xenograft models in mice. Compound 20g exhibited equivalent antitumor efficacy in vivo (T/C Combining double low line 44.37%), compared to Sorafenib (T/C Combining double low line 37.35%), by 23-day repetitive administration of a single dose of 50 mg/kg without significant body weight loss.
2-Amino-1-phenyl-pyrrolo[3,2-b]quinoxaline-3-carboxamide derivates
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Paragraph 0171; 0173, (2015/11/16)
The invention relates to compound characterized by a general formula (1), wherein n of R1n is 0, 1, 2, 3 or 4, in particular n of R1n is 0 or 1, and each R1 independently from any other R1
Pyrrolo[3,2-b ]quinoxaline derivatives as types I1/2 and II Eph tyrosine kinase inhibitors: Structure-based design, synthesis, and in vivo validation
Unzue, Andrea,Dong, Jing,Lafleur, Karine,Zhao, Hongtao,Frugier, Emilie,Caflisch, Amedeo,Nevado, Cristina
, p. 6834 - 6844 (2014/10/15)
The X-ray crystal structures of the catalytic domain of the EphA3 tyrosine kinase in complex with two type I inhibitors previously discovered in silico (compounds A and B) were used to design type I1/2 and II inhibitors. Chemical synthesis of a
COMPOUNDS FOR USE IN INHIBITING HIV CAPSID ASSEMBLY
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, (2014/09/03)
The present invention relates a compound or a pharmaceutically acceptable salt or solvate thereof for use in inhibiting HIV capsid assembly, wherein the compound is a pyrimidine being at least substituted in two positions, preferably in 2 and 4 position o
