- Synthesis of novel sulfonamide derivatives containing pyridin-3-ylmethyl 4-(benzoyl)piperazine-1-carbodithioate moiety as potent PKM2 activators
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Pyruvate kinase M2 isoform (PKM2) plays a key role in cancer progression through both metabolic and non-metabolic functions, thus it is recognized as a potential target for cancer diagnosis and treatment. In this study, we discovered a sulfonamide-dithiocarbamate compound 8a as a novel PKM2 activator from a random screening of an in-house compound library. Then, a series of lead compound 8a analogs were designed and synthesized for screening as potent PKM2 activators. Among them, compound 8b (AC50 = 0.136 μM) and 8k (AC50 = 0.056 μM) showed higher PKM2 activation activities than positive control NZT (AC50 = 0.228 μM), and they (IC50 50 > 10 μM). Especially, compound 8k inhibited the proliferation of multiple cancer cells, but showed little toxicity on normal cells. In addition, we found that compound 8k inhibit the colony formation of MCF7 cells. Western blot analysis demonstrated that 8k could reduce PKM2 nuclear localization and block the downstream signaling pathway of PKM2, resulting in suppression of tumor cell proliferation. Overall, compound 8k may be a promising candidate for further mechanistic investigation of PKM2 and cancer therapy.
- Li, Ridong,Ning, Xianling,He, Jianan,Lin, Zhiqiang,Su, Yue,Li, Runtao,Yin, Yuxin
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Read Online
- Memantine urea derivative as well as preparation method and application thereof
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The invention provides a memantine urea derivative as well as a preparation method and application thereof, and relates to the technical field of medicines. The memantine urea derivative provided by the invention has a typical urea structure as a primary
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Paragraph 0288; 0289
(2021/07/31)
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- Optimization and SAR research at the piperazine and phenyl rings of JNJ4796 as new anti-influenza A virus agents, part 1
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JNJ4796, a small molecule fuse inhibitor targeting the conserved stem region of hemagglutinin, effectively neutralized a broad spectrum of group 1 influenza A virus (IAV), and protected mice against lethal and sublethal influenza challenge after oral admi
- Wang, Aoyu,Li, Yuhuan,Lv, Kai,Gao, Rongmei,Wang, Apeng,Yan, Haiyan,Qin, Xiaoyu,Xu, Shijie,Ma, Chao,Jiang, Jiandong,Wei, Zengquan,Zhang, Kai,Liu, Mingliang
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supporting information
(2021/06/15)
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- Pyridine compound, preparation method and application thereof, and pharmaceutical composition
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The invention provides a pyridine compound as well as a preparation method and application thereof, and belongs to the technical field of medical chemistry. The pyridine compound provided by the invention has excellent in-vitro antiviral activity and potential druggability, and is expected to become a clinical candidate molecule for overcoming influenza.
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Paragraph 0202-0204
(2021/02/10)
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- Looking toward the Rim of the Active Site Cavity of Druggable Human Carbonic Anhydrase Isoforms
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We report the synthesis and biochemical evaluation of a series of substituted 4-(4-aroylpiperazine-1-carbonyl)benzenesulfonamides (5a-s) developed as inhibitors of druggable carbonic anhydrase (CA) isoforms, as tools for the identification of new therapeu
- Mancuso, Francesca,Di Fiore, Anna,De Luca, Laura,Angeli, Andrea,Monti, Simona M.,De Simone, Giuseppina,Supuran, Claudiu T.,Gitto, Rosaria
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supporting information
p. 1000 - 1005
(2020/03/23)
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- SMALL MOLECULE PROTEOLYSIS-TARGETING CHIMERAS AND METHODS OF USE THEREOF
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Novel small molecule proteolysis-targeting chimeras (PROTACs) are provided, along with methods for their use as Bruton's tyrosine kinase (BTK) degraders. The small molecule PROTACs described herein are useful in treating and/or preventing BTK-related diseases, such as cancer, neurodegenerative disorders, inflammatory diseases, and metabolic disorders. Also provided are methods for inducing BTK degradation in a cell using the compounds and compositions described herein. Exemplary compounds include: (I).
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Page/Page column 66; 67-68
(2020/12/30)
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- Aminodithioformate compound used as FAK inhibitor
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A purpose of the invention is to provide an aminodithioformate compound serving as an FAK inhibitor, a pharmaceutical composition, a preparation method and applications thereof, wherein the compound has a structure represented by the following general formula (I).
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Paragraph 0089-0091; 0110-0112
(2020/05/09)
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- Discovery of 2,4-diarylaminopyrimidine derivatives bearing dithiocarbamate moiety as novel FAK inhibitors with antitumor and anti-angiogenesis activities
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A series of 2,4-diarylaminopyrimidine derivatives containing dithiocarbamate moiety were designed by molecular hybridization strategy and synthesized for screening as inhibitors of focal adhesion kinase (FAK). Most of these compounds exhibit significant a
- Su, Yue,Li, Ridong,Ning, Xianling,Lin, Zhiqiang,Zhao, Xuyang,Zhou, Juntuo,Liu, Jia,Jin, Yan,Yin, Yuxin
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- DEGRADATION OF BRUTON'S TYROSINE KINASE (BTK) BY CONJUGATION OF BTK INHIBITORS WITH E3 LIGASE LIGAND AND METHODS OF USE
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The present application provides bifunctional compounds of Formula X or an enantiomer, diastereomer, or stereoisomer thereof, or pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, which act as protein degradation inducing moieties for Bruton's tyrosine kinase (BTK). The present application also relates to methods for the targeted degradation of BTK through the use of bifunctional compounds that link a ubiquitin ligase-binding moiety to a ligand that is capable of binding to BTK which can be utilized in the treatment of disorders modulated by BTK.
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Page/Page column 185; 186
(2019/08/12)
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- N?-Acryloyllysine Piperazides as Irreversible Inhibitors of Transglutaminase 2: Synthesis, Structure-Activity Relationships, and Pharmacokinetic Profiling
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Transglutaminase 2 (TGase 2)-catalyzed transamidation represents an important post-translational mechanism for protein modification with implications in physiological and pathophysiological conditions, including fibrotic and neoplastic processes. Consequently, this enzyme is considered a promising target for the diagnosis of and therapy for these diseases. In this study, we report on the synthesis and kinetic characterization of N?-acryloyllysine piperazides as irreversible inhibitors of TGase 2. Systematic structural modifications on 54 new compounds were performed with a major focus on fluorine-bearing substituents due to the potential of such compounds to serve as radiotracer candidates for positron emission tomography. The determined inhibitory activities ranged from 100 to 10?000 M-1 s-1, which resulted in comprehensive structure-activity relationships. Structure-activity correlations using various substituent parameters accompanied by covalent docking studies provide an advanced understanding of the molecular recognition for this inhibitor class within the active site of TGase 2. Selectivity profiling of selected compounds for other transglutaminases demonstrated an excellent selectivity toward transglutaminase 2. Furthermore, an initial pharmacokinetic profiling of selected inhibitors was performed, including the assessment of potential membrane permeability and liver microsomal stability.
- Wodtke, Robert,Hauser, Christoph,Ruiz-Gómez, Gloria,J?ckel, Elisabeth,Bauer, David,Lohse, Martin,Wong, Alan,Pufe, Johanna,Ludwig, Friedrich-Alexander,Fischer, Steffen,Hauser, Sandra,Greif, Dieter,Pisabarro, M. Teresa,Pietzsch, Jens,Pietsch, Markus,L?ser, Reik
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supporting information
p. 4528 - 4560
(2018/05/07)
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- DEGRADATION OF BRUTON'S TYROSINE KINASE (BTK) BY CONJUGATION OF BTK INHIBITORS WITH E3 LIGASE LIGAND AND METHODS OF USE
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The present application provides bifunctional compounds of Formula (I), or an enantiomer, diastereomer, or stereoisomer thereof, or pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, which act as protein degradation inducing moieties for Bruton's tyrosine kinase (BTK). The present application also relates to methods for the targeted degradation of BTK through the use of the bifunctional compounds that link a ubiquitin ligase-binding moiety to a ligand that is capable of binding to BTK which can be utilized in the treatment of disorders modulated by BTK.
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Page/Page column 126
(2018/06/12)
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- DEGRADATION OF BRUTON'S TYROSINE KINASE (BTK) BY CONJUGATION OF BTK INHIBITORS WITH E3 LIGASE LIGAND AND METHODS OF USE
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The present application provides bifunctional compounds of Formula (X), or an enantiomer, diastereomer, or stereoisomer thereof, or pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, which act as protein degradation inducing moieties for Bruton's tyrosine kinase (BTK). The present application also relates to methods for the targeted degradation of BTK through the use of the bifunctional compounds that link a ubiquitin ligase-binding moiety to a ligand that is capable of binding to BTK which can be utilized in the treatment of disorders modulated by BTK.
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Page/Page column 154; 155
(2018/06/12)
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- Substituted O-hydroxyphenyl ketone compound as well as preparation method and application thereof
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The invention discloses a substituted O-hydroxyphenyl ketone compound, a preparation method of the substituted O-hydroxyphenyl ketone compound, and an application of the substituted O-hydroxyphenyl ketone compound to preparation of a BRD4 protein activity
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Paragraph 0079-0081; 0085-0087
(2018/11/22)
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- Oxazolo[4,5-b]pyridine-Based Piperazinamides as GSK-3β Inhibitors with Potential for Attenuating Inflammation and Suppression of Pro-Inflammatory Mediators
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Recent studies reveal that glycogen synthase kinase-3β (GSK-3β) acts as a pro-inflammatory enzyme, and by inhibiting this kinase, inflammation can be controlled. In this regard, a series of 17 piperazine-linked oxazolo[4,5-b]pyridine-based derivatives was
- Tantray, Mushtaq A.,Khan, Imran,Hamid, Hinna,Alam, Mohammad Sarwar,Dhulap, Abhijeet,Ganai, Ajaz Ahmad
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- Piperazine substituted 1, 3 - di-substituted urea compound and piperazine substituted amide compounds and a method for its preparation and use
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The present invention relates to a class of piperazine substituted 1,3-disubstitued urea compounds and piperazine substituted amide compounds, or pharmaceutically acceptable salts of the piperazine substituted 1,3-disubstitued urea compounds and the piper
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Paragraph 0068; 0091-0093
(2017/04/22)
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- Synthesis and biological evaluation of substituted 4-(thiophen-2-ylmethyl)- 2H-phthalazin-1-ones as potent PARP-1 inhibitors
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We have developed a series of substituted 4-(thiophen-2-ylmethyl)-2H- phthalazin-1-ones as potent PARP-1 inhibitors. Preliminary biological evaluation indicated that most compounds possessed inhibitory potencies comparable to, or higher than AZD-2281. Among these compounds, 18q appeared to be the most notable one, which displayed an 8-fold improvement in enzymatic activity compared to AZD-2281. These efforts lay the foundation for our further investigation.
- Wang, Ling-Xiao,Zhou, Xin-Bo,Xiao, Meng-Liang,Jiang, Ning,Liu, Feng,Zhou, Wen-Xia,Wang, Xiao-Kui,Zheng, Zhi-Bing,Li, Song
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p. 3739 - 3743
(2014/09/17)
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- METHODS OF LOWERING PROPROTEIN CONVERTASE SUBTILISIN/KEXIN TYPE 9 (PCSK9)
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The invention relates to new methods of modulating cholesterol by inhibiting proprotein convertase subtilisin/kexin type 9 (PCSK9) with fatty acid derivatives; and new methods for treating or preventing a metabolic disease comprising the administration of an effective amount of a fatty acid derivative. The present invention is also directed to fatty acid bioative derivatives and their use in the treatment of metabolic diseases.
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Paragraph 0259
(2014/01/07)
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- CARBAZOLE AND CARBOLINE KINASE INHIBITORS
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The present invention provides compounds of Formula (I) and pharmaceutically acceptable salts thereof. The Formula (I) compounds inhibit tyrosine kinase activity of Jak2, thereby making them useful as antiproliferative agents for the treatment of cancer and other diseases.
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Page/Page column 140; 141
(2010/08/04)
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- OXAZOLE TYROSINE KINASE INHIBITORS
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The invention provides a compound which is an amide of the formula (1), or a salt, solvate, N-oxide or tautomer thereof; wherein: a is 0 or 1; b is 0 or 1 : provided that the sum of a and b is 0 or 1; T is O or NH Ar1 is a monocyclic or bicyclic 5- to 10-membered aryl or heteroaryl group containing up to 4 heteroatoms selected from O, N and S, and being optionally substituted by one or more substituents R1; Ar2 Js a monocyclic or bicyclic 5- to 10-membered aryl or heteroaryl group containing up to 4 heteroatoms selected from O, N and S and being optionally substituted by one or more substituents R2; and R1 and R2are as defined in the claims. The compounds are inhibitors of kinases and in particular FLT3, FLT4 and Aurora kinases.
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Page/Page column 161
(2009/01/20)
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- DIAMINOPYRIMIDINECARBOXA MIDE DERIVATIVE
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A compound which may be used for the prevention or treatment of respiratory diseases in which STAT 6 is concerned, particularly asthma, chronic obstructive pulmonary disease and the like is provided. A pyrimidine derivative or a salt thereof, which has an arylamino or arylethylamino group which may be substituted with a specified substituent, at the 2-position, amino group substituted with benzyl group or the like, at the 4-position, and carbamoyl group which may be substituted, at the 5-position, is provided.
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Page/Page column 22
(2008/06/13)
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- HETEROCYCLICALLY SUBSTITUTED INDOLINONES, THEIR PRODUCTION AND USE AS MEDICAMENTS
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The invention relates to heterocyclically substituted indolinones of general formula (I), in which R1 to R5 and X are defined as cited in claim 1, to their tautomers, diastereomers, enantiomers and to their mixtures, prodrugs and salts, in particular their physiologically compatible salts. Said compounds exhibit valuable pharmacological characteristics, in particular an inhibiting action on various receptor tyrosine kinases and cyclin-CDK complexes and on the proliferation of endothelial cells and various tumour cells. The invention also relates to medicaments containing said compounds, to the use of the latter and to a method for producing the same.
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Page/Page column 96
(2008/06/13)
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- Substituted indolinones
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The present invention relates to indolinones substituted in the 6-position of general formula wherein R1 to R5 and X are defined as in claim 1, the isomers and the salts thereof, particularly the physiologically acceptable salts thereof which have valuable pharmacological properties, in particular an inhibiting effect on various receptor tyrosine kinases and cyclin/CDK complexes and on the proliferation of endothelial cells and various, pharmaceutical compositions containing these compounds, their use and processes for preparing them.
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