- 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
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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.
- Chin, Frederick T.,Kooijman, Esther J. M.,Nezam, Madina,Reyes, Samantha T.,Shen, Bin,Windhorst, Albert D.,van der Wildt, Berend
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- Discovery and Identification of Small Molecules as Methuosis Inducers with in Vivo Antitumor Activities
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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,
- 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
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supporting information
p. 5424 - 5434
(2018/06/18)
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- DUAL SRC/P38 KINASE INHIBITOR COMPOUNDS AND THEIR USE AS THERAPEUTIC AGENTS
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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.
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- 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
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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.
- 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
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p. 1984 - 2004
(2016/03/22)
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- 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
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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.
- Yang, Weimin,Chen, Yadong,Zhou, Xiang,Gu, Yazhou,Qian, Wenqi,Zhang, Fan,Han, Wei,Lu, Tao,Tang, Weifang
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p. 581 - 596
(2014/12/12)
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- ISOQUINOLINE-5-CARBOXAMIDE DERIVATIVE HAVING INHIBITORY ACTIVITY FOR PROTEIN KINASE
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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.
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Paragraph 0077
(2015/06/03)
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- ISOQUINOLINE-5-CARBOXAMIDE DERIVATIVE HAVING INHIBITORY ACTIVITY FOR PROTEIN KINASE
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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.
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Paragraph 0154-0156
(2015/07/15)
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- 2-Amino-1-phenyl-pyrrolo[3,2-b]quinoxaline-3-carboxamide derivates
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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
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-
Paragraph 0171; 0173
(2015/11/16)
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- COMPOUNDS FOR USE IN INHIBITING HIV CAPSID ASSEMBLY
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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
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Page/Page column 39-40
(2014/09/03)
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- Pyrrolo[3,2-b ]quinoxaline derivatives as types I1/2 and II Eph tyrosine kinase inhibitors: Structure-based design, synthesis, and in vivo validation
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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
- Unzue, Andrea,Dong, Jing,Lafleur, Karine,Zhao, Hongtao,Frugier, Emilie,Caflisch, Amedeo,Nevado, Cristina
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supporting information
p. 6834 - 6844
(2014/10/15)
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- THIENO (2, 3B) PYRAZINE COMPOUNDS AS B-RAF INHIBITORS
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The invention relates to compounds according to general Formula (I) or a pharmaceutically acceptable salt thereof. The compounds can be used for the treatment of cancer.
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- THIENO (2, 3B) PYRAZINE COMPOUNDS AS B - RAF INHIBITORS
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The invention relates to compounds according to general Formula (I) or a pharmaceutically acceptable salt thereof. The compounds can be used for the treatment of cancer.
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- A type-ii kinase inhibitor capable of inhibiting the T315I "Gatekeeper" mutant of Bcr-Abl
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The second generation of Bcr-Abl inhibitors nilotinib, dasatinib, and bosutinib developed to override imatinib resistance are not active against the T315I "gatekeeper" mutation. Here we describe a type-II T315I inhibitor 2 (GNF-7), based upon a 3,4-dihydr
- Choi, Hwan Geun,Ren, Pingda,Adrian, Francisco,Sun, Fangxian,Lee, Hyun Soo,Wang, Xia,Ding, Qiang,Zhang, Guobao,Xie, Yongping,Zhang, Jianming,Liu, Yi,Tuntland, Tove,Warmuth, Markus,Manley, Paul W.,Mestan, Jürgen,Gray, Nathanael S.,Sim, Taebo
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experimental part
p. 5439 - 5448
(2010/11/05)
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- Synthesis of aminoquinazoline derivatives and their antiproliferative activities against melanoma cell line
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The synthesis of a novel series of aminoquinazoline derivatives 1a-r and their antiproliferative activities against A375 human melanoma cell line were described. Among them, six compounds showed superior antiproliferative activities to Sorafenib as a reference compound. In particular, the representative compound 1q bearing chromen-4-one moiety exhibited excellent antiproliferative activity (IC50 = 0.006 μM) and good selectivity over HS27 fibroblast cell line.
- Lee, Junsang,Nam, Bong Soo,Kim, Hwan,Oh, Chang-Hyun,Lee, So Ha,Cho, Seung Joo,Sim, Tae Bo,Hah, Jung-Mi,Kim, Dong Jin,Tae, Jinsung,Yoo, Kyung Ho
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scheme or table
p. 5722 - 5725
(2010/11/24)
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- Identification of amidoheteroaryls as potent inhibitors of mutant (V600E) B-Raf kinase with in vivo activity
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A series of amidoheteroaryl compounds were designed and synthesized as inhibitors of B-Raf kinase. Several compounds from the series show excellent potency in biochemical, phenotypic and mode of action cellular assays. Potent examples from the series have also demonstrated good plasma exposure following an oral dose in rodents and activity against the Ras-Raf pathway in tumor bearing mice.
- Lyne, Paul D.,Aquila, Brian,Cook, Donald J.,Dakin, Les A.,Ezhuthachan, Jay,Ioannidis, Stephanos,Pontz, Timothy,Su, Mei,Ye, Qing,Zheng, Xiaolan,Block, Michael H.,Cowen, Scott,Deegan, Tracy L.,Lee, John W.,Scott, David A.,Custeau, Dominique,Drew, Lisa,Poondru, Srinivasu,Shen, Minhui,Wu, Allan
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scheme or table
p. 1026 - 1029
(2009/08/15)
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- Discovery of pyrimidine benzimidazoles as Src-family selective Lck inhibitors. Part II
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A series of 4-amino-6-benzimidazole-pyrimidines was designed to target lymphocyte-specific tyrosine kinase (Lck), a member of the Src-family kinases (SFKs). These type II inhibitors were optimized using a cellular Lck-dependent proliferation assay and are
- Zhang, Guobao,Ren, Pingda,Gray, Nathanael S.,Sim, Taebo,Wang, Xia,Liu, Yi,Che, Jianwei,Dong, Weitong,Tian, Shin-Shay,Sandberg, Mark L.,Spalding, Tracy A.,Romeo, Russell,Iskandar, Maya,Wang, Zhiliang,Seidel, H. Martin,Karanewsky, Donald S.,He, Yun
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scheme or table
p. 6691 - 6695
(2010/06/12)
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- 3-Aminocarbonyl-substituted fused pyrazolo-derivatives as protein kinase modulators
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The present invention relates to pyrazolo[1,5-a]pyrimidine-3-carboxylic acid compounds of formula I or pharmaceutically acceptable salts thereof and their use for the treatment of protein kinase modulation responsive diseases.
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Page/Page column 21-22
(2008/12/04)
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- 3-AMINO-PYRAZOLE-4-CARBOXAMIDE DERIVATIVES USEFUL AS INHIBITORS OF PROTEIN KINASES
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The invention relates to novel heterocyclic compounds of the formula (I), in which all of the variables are as defined in the specification, in free form or in salt form, to their preparation, to their use as medicaments and to medicaments comprising them
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Page/Page column 40
(2008/12/05)
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- PYRAZOLO[1,5-A]PYRIDINE-3-CARBOXYLIC ACIDS AS EPHB AND VEGFR2 KINASE INHIBITORS
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The invention relates to novel pyrazolo[1,5-a]pyridine-3-carboxylic acid compounds of the Formula (I) in which all of the variables are as defined in the specification, in free form or in salt form, to their preparation, to their use as medicaments and to medicaments comprising them.
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Page/Page column 57
(2008/06/13)
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- NOVEL PHENYLAMINOPYRIMIDINE DERIVATIVES AS INHIBITORS OF BCR-ABL KINASE
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The present invention relates to novel intermediates useful for the preparation of novel phenylaminopyrimidine derivatives, novel phenylaminopyrimidine derivatives. Pharmaceutical composition containing the novel phenylaminopyrimidine derivatives and processes for their preparation. The invention particularly relates to novel Phenyl pyrimidine amine derivatives of the general formula (I). The novel compounds of the formula 1 can be used in the therapy of Chronic Myeloid Leukemia (CML). Since the IC50; 191 values of these molecules are in the range 0.1 to 10.0 nm, these novel compounds are potentially useful for the treatment of CML.
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Page/Page column 25-26
(2008/06/13)
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- PYRIMIDINE UREA DERIVATIVES AS KINASE INHIBITORS
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The invention relates to compounds of formula (I) wherein the substituents X1, R1, R2, R3 and R4 have the meaning as set forth and explained in the description of the invention, to processes for the preparation of these compounds, pharmaceutical compositions containing same, the use thereof optionally in combination with one or more other pharmaceutically active compounds for the therapy of a disease which responds to an inhibition of protein kinase activity, and a method for the treatment of such a disease.
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Page/Page column 158
(2008/06/13)
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- COMPOUNDS AND COMPOSITIONS AS PROTEIN KINASE INHIBITORS
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The invention provides a novel class of compounds, pharmaceutical compositions comprising such compounds and methods of using such compounds to treat or prevent diseases or disorders associated with abnormal or deregulated kinase activity, particularly diseases or disorders that involve abnormal activation of the Abl, Bcr-Abl, FGFR3, PDGFRβ and b-Raf kinases.
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Page/Page column 23-24
(2008/06/13)
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- QUINAZOLINONE DERIVATIVES AND THEIR USE AS B-RAF INHIBITORS
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The invention relates to chemical compounds of the formula (I): or pharmaceutically acceptable salts thereof, which possess B Raf inhibitory activity and are accordingly useful for their anti cancer activity and thus in methods of treatment of the human or animal body. The invention also relates to processes for the manufacture of said chemical compounds, to pharmaceutical compositions containing them and to their use in the manufacture of medicaments of use in the production of an anti-cancer effect in a warm blooded animal such as man.
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Page/Page column 70
(2008/06/13)
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- SUBSTITUTED QUINAZOLONES AS ANTI-CANCER AGENTS
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The invention relates to chemical compounds of the formula (I): or pharmaceutically acceptable salts thereof, which possess B Raf inhibitory activity and are accordingly useful for their anti cancer activity and thus in methods of treatment of the human or animal body. The invention also relates to processes for the manufacture of said chemical compounds, to pharmaceutical compositions containing them and to their use in the manufacture of medicaments of use in the production of an anti-cancer effect in a warm blooded animal such as man.
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Page/Page column 66
(2010/02/15)
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- BEZAMIDE DERIVATIVES FOR THE TREATMENT OF DISEASES MEDIATED BY CYTOKINES
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The invention concerns the use of amide derivatives of formula (I) wherein: R1 and R2 are substituents such as hydroxy, C1-6alkoxy, mercapto, C1-6alkylthio, amino, C1-6alkylamino and di-(C1-6alkyl)amino; m and p are independently 0-3; R3 is C1-4alkyl; q is 0-4; and R4 is aryl or cycloalkyl; or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in the treatment of diseases or medical conditions mediated by cytokines
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- Amide derivatives for the treatment of diseases mediated by cytokines
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The invention concerns the use of amide derivatives of formula (I) wherein: R1and R2are substituents such as hydroxy, C1-6alkoxy, mercapto, C1-6alkylthio, amino, C1-6alkylamino and di-(C1-6alkyl)amino; m and p are independently 0-3R3is C1-4alkyl; q is 0-4; and R4is aryl or cycloalkyl; or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in the treatment of diseases or medical conditions mediated by cytokines
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