- Design, synthesis and anti-tumor evaluation of 1,2,4-triazol-3-one derivatives and pyridazinone derivatives as novel CXCR2 antagonists
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Chemokine receptor 2 (CXCR2) is the receptor of glutamic acid–leucine–arginine sequence-contained chemokines CXCs (ELR+ CXCs). In recent years, CXCR2-target treatment strategy has come a long way in cancer therapy. CXCR2 antagonists could block
- Chu, Bizhu,Jiang, Yuyang,Li, Qinyuan,Liu, Zijian,Luo, Jingyi,Shi, Zhichao,Xin, Qilei,Ye, Lizhen,Zhan, Feng,Zhang, Xun,Zhu, Qingyun
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- PYRAZOLOPYRIDAZINE DERIVATIVES, PREPARATION METHOD THEREOF AND COMPOSITION FOR PREVENTING OR TREATING CANCER COMPRISING THE SAME
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The present invention is a pyrazolopyridazine derivative. A pharmaceutical composition for preventing or treating cancer contains the pyrazolopyridazin derivative compound Hsp90 according to the present invention as an active ingredient, which can be used as Hsp90 a pharmaceutical composition for preventing or treating Hsp90-related diseases such as melanoma, brain tumor, breast cancer, lung cancer and the like. (by machine translation)
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Paragraph 0316-0320
(2020/11/14)
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- Discovery and Development of a Series of Pyrazolo[3,4- d]pyridazinone Compounds as the Novel Covalent Fibroblast Growth Factor Receptor Inhibitors by the Rational Drug Design
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Alterations of fibroblast growth factor receptors (FGFRs) play key roles in numerous cancer progression and development, which makes FGFRs attractive targets in the cancer therapy. In the present study, based on a newly devised FGFR target-specific scorin
- Wang, Yulan,Dai, Yang,Wu, Xiaowei,Li, Fei,Liu, Bo,Li, Chunpu,Liu, Qiufeng,Zhou, Yuanyang,Wang, Bao,Zhu, Mingrui,Cui, Rongrong,Tan, Xiaoqin,Xiong, Zhaoping,Liu, Jia,Tan, Minjia,Xu, Yechun,Geng, Meiyu,Jiang, Hualiang,Liu, Hong,Ai, Jing,Zheng, Mingyue
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p. 7473 - 7488
(2019/09/03)
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- 5-MEMBERED HETEROCYCLE FUSED WITH [3,4-D]PYRIDAZINONE, AND MANUFACTURING METHOD, PHARMACEUTICAL COMPOSITION, AND APPLICATION THEREOF
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The present invention provides a compound comprising a 5-membered heterocycle fused with a pyridazinone, wherein the compound is used as an FGFR kinase inhibitor, and a manufacturing method and application thereof. The invention specifically provides a co
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Paragraph 0094
(2019/04/29)
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- Pyrazole-4-Carboxamide (YW2065): A Therapeutic Candidate for Colorectal Cancer via Dual Activities of Wnt/β-Catenin Signaling Inhibition and AMP-Activated Protein Kinase (AMPK) Activation
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Dysregulation of the Wnt/β-catenin signaling pathway has been widely recognized as a pathogenic mechanism for colorectal cancer (CRC). Although numerous Wnt inhibitors have been developed, they commonly suffer from toxicity and unintended effects. Moreover, concerns have been raised in targeting this pathway because of its critical roles in maintaining stem cells and regenerating tissues and organs. On the basis of the anthelmintic drug pyrvinium and previous lead FX1128, we have developed a compound YW2065 (1c) which demonstrated excellent anti-CRC effects in vitro and in vivo. YW2065 achieves its inhibitory activity for Wnt signaling by stabilizing Axin-1, a scaffolding protein that regulates proteasome degradation of β-catenin. Simultaneously, YW2065 also led to the activation of the tumor suppressor AMPK, providing an additional anticancer mechanism. In addition, YW2065 showed favorable pharmacokinetic properties without obvious toxicity. The anti-CRC effect of YW2065 was highlighted by its promising efficacy in a mice xenograft model.
- Yang, Wei,Li, Yingjun,Ai, Yong,Obianom, Obinna N.,Guo, Dong,Yang, Hong,Sakamuru, Srilatha,Xia, Menghang,Shu, Yan,Xue, Fengtian
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p. 11151 - 11164
(2019/12/27)
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- WNT SIGNALING PATHWAY INHIBITORS FOR TREATMENTS OF DISEASE
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Compounds and compositions are provided as inhibitors of the Wnt/β-catenin pathway for the treatment of diseases that implicate the same.
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Paragraph 00264
(2017/09/15)
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- HETERO-HALO INHIBITORS OF HISTONE DEACETYLASE
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This invention provides compounds that are inhibitors of HDAC2. The compounds (e.g., compounds according to Formula I, II or any of Compounds 100-128 or any of those in Tables 2 or 3) accordingly are useful for treating, alleviating, or preventing a condition in a subject such as a neurological disorder, memory or cognitive function disorder or impairment, extinction learning disorder, fungal disease or infection, inflammatory disease, hematological disease, or neoplastic disease, or for improving memory or treating, alleviating, or preventing memory loss or impairment.
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Paragraph 263
(2017/01/26)
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- Design, synthesis and structure-activity relationships of novel 4-phenoxyquinoline derivatives containing 1,2,4-triazolone moiety as c-Met kinase inhibitors
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A series of novel 4-phenoxyquinoline derivatives containing 1,2,4-triazolone moiety were synthesized and evaluated for their in?vitro cytotoxic activity against four cancer cell lines (HT-29, H460, A549 and MKN-45). Most of the compounds exhibited moderate-to-significant cytotoxicity. Compounds 33, 37, 39, 44, 46, 47, 53, 55, 61, 64 and 66 were further examined for their inhibitory activity against c-Met kinase. The most promising compound 47 (with c-Met IC50value of 1.57?nM) showed remarkable cytotoxicity against HT-29, H460, A549 and MKN-45?cell lines with IC50values of 0.08?μM, 0.14?μM, 0.11?μM and 0.031?μM, respectively, and thus it was 1.1- to 2.3- fold more potent than foretinib. Their preliminary structure-activity relationships (SARs) studies indicate that electron-withdrawing groups on the terminal phenyl rings are beneficial for improving the antitumor activity.
- Liu, Ju,Nie, Minhua,Wang, Yanjing,Hu, Jinxing,Zhang, Feng,Gao, Yanlin,Liu, Yajing,Gong, Ping
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p. 431 - 446
(2016/08/04)
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- Exploring the 2- and 5-positions of the pyrazolo[4,3-d]pyrimidin-7-amino scaffold to target human A1 and A2A adenosine receptors
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A new series of 7-aminopyrazolo[4,3-d]pyrimidine derivatives (1-31) were synthesized to evaluate some structural modifications at the 2- and 5-positions aimed at shifting affinity towards the human (h) A2A adenosine receptor (AR) or both hA2A and hA1 ARs. The most active compounds were those featured by a 2-furyl or 5-methylfuran-2-yl moiety at position 5, combined with a benzyl or a substituted-benzyl group at position 2. Several of these derivatives (22-31) displayed nanomolar affinity for the hA2A AR (Ki = 3.62-57 nM) and slightly lower for the hA1 ARs, thus showing different degrees (3-22 fold) of hA2A versus hA1 selectivity. In particular, the 2-(2-methoxybenzyl)-5-(5-methylfuran-2-yl) derivative 25 possessed the highest hA2A and hA1 AR affinities (Ki = 3.62 nM and 18 nM, respectively) and behaved as potent antagonist at both these receptors (cAMP assays). Its 2-(2-hydroxybenzyl) analog 26 also showed a high affinity for the hA2A AR (Ki = 5.26 nM) and was 22-fold selective versus the hA1 subtype. Molecular docking investigations performed at the hA2A AR crystal structure and at a homology model of the hA1 AR allowed us to represent the hypothetical binding mode of our derivatives and to rationalize the observed SARs.
- Squarcialupi, Lucia,Falsini, Matteo,Catarzi, Daniela,Varano, Flavia,Betti, Marco,Varani, Katia,Vincenzi, Fabrizio,Dal Ben, Diego,Lambertucci, Catia,Volpini, Rosaria,Colotta, Vittoria
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p. 2794 - 2808
(2016/06/08)
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- Asymmetric catalytic 1,3-dipolar cycloaddition reaction of nitrile imines for the synthesis of chiral spiro-pyrazoline-oxindoles
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A new 1,3-dipolar cycloaddition of nitrile imines with 3-alkenyl-oxindoles was catalyzed by a new chiral Mg(ClO4)2 complex of an N,N'-dioxide ligand. The reaction is so far the sole catalytic synthesis of spiro-pyrazoline-oxindole derivatives. A wide variety of substrates were explored to obtain good yields (up to 98%) and excellent enantioselectivities (up to 99%). This cycloaddition expands the scope of propargyl anion type 1,3-dipole in the construction of 2-pyrazoline subunit.
- Wang, Gang,Liu, Xiaohua,Huang, Tianyu,Kuang, Yulong,Lin, Lili,Feng, Xiaoming
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supporting information
p. 76 - 79
(2013/04/10)
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- Optimization of non-ATP competitive CDK/cyclin groove inhibitors through REPLACE-mediated fragment assembly
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A major challenge in drug discovery is to develop and improve methods for targeting protein-protein interactions. Further exemplification of the REPLACE (REplacement with Partial Ligand Alternatives through Computational Enrichment) strategy for generatin
- Liu, Shu,Premnath, Padmavathy Nandha,Bolger, Joshua K.,Perkins, Tracy L.,Kirkland, Lindsay O.,Kontopidis, George,McInnes, Campbell
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p. 1573 - 1582
(2013/04/10)
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- HETEROCYCLIC INHIBITORS OF AN Hh-SIGNAL CASCADE, MEDICINAL COMPOSITIONS BASED THEREON AND METHODS FOR TREATING DISEASES CAUSED BY THE ABERRANT ACTIVITY OF AN Hh-SIGNAL SYSTEM
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The invention relates to novel heterocyclic compounds and to the use thereof, to pharmaceutical compositions containing said chemical compounds as an active ingredient and to the use thereof for producing medicinal preparations for the human being and warm-blood animals for treating diseases caused by the aberrant activity of an Hedgehog (Hh)-signal system, in particular oncological diseases. The invention also relates to the use of the above-mentioned compounds in the form of ‘molecular pharmacological tools’ for examining (in vitro and in vivo) the biochemical features of the Hh-signal system, in particular, the interaction of Hh protein and transmembrane proteins, namely, suppressor Patched (Ptc) and protooncogenic proteins. The eight groups of the claimed compounds comprise the derivatives of 2,6-dihydro-7H-pyrazolo[3,4-d]pyridazine-7-one and 1,4-dihydropyrazolo[3,4-b][1,4]thiazine-5-one; N-acidylated 4-imidazo[1,2-a]pyrimidine-2-il-anilines; ([4H-thino[3,2-b]pyrrol-5-il) carbonyl]piperidine-4-carbonic acid amides; 2-(4carbomoilpyperidine-1-il)-isonicotinic acid amides; N-sylphonyl-1,2,3,4-tetrahydroquinoline-6-carbonic acid amides; and pyridine 2-amino-4,5,6,7-tetrahydrothieno[2,3-c] N-acidylated 3-azole derivatives.
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Page/Page column 10
(2011/04/14)
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- A new method for the synthesis of 1-aryl-1,2,4-triazole derivatives
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A new and convenient one-step recyclization method for the synthesis of ethyl 1-aryl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxylates is reported. Various ethyl chloro(2-arylhydrazinylidene)ethanoates react with thiazolidine-2,4-dione in the presence of potassium hydroxide to produce the 1-aryl-1,2,4-triazole derivatives in moderate to good yields. The procedure is economical, environmentally friendly and simple to perform. Georg Thieme Verlag Stuttgart - New York.
- Matiychuk, Vasyl S.,Potopnyk, Mykhaylo A.,Luboradzki, Roman,Obushak, Mykola D.
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experimental part
p. 1799 - 1803
(2011/07/08)
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- Molecular design of pyrazolo[3,4-d]pyridazines
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Reactions of arenediazonium chlorides with ethyl 2-methyl-and 2-chloro-4-oxobutanoates gave, respectively, ethyl 2-(arylhydrazono)propanoates and chloro(arylhydrazono)acetates. Ethyl 2-(arylhydrazono)-propanoates reacted with the Vilsmeier-Haak reagent to give ethyl 1-aryl-4-formyl-1 H-pyrazole-3-carboxylates. Ethyl 1-aryl-4-acetyl-5-methyl-1H-pyrazole-3- carboxylates were obtained by reaction of chloro(arylhydrazono) acetates with acetylacetone. Reactions of the obtained pyrazole derivatives with hydrazine and methylhydrazine led to the formation of the corresponding 3,4-R 2 1 -6-R2-2-aryl-2,6-dihydro-7H-pyrazolo-[3,4-d]pyridazin-7- ones (R1, R2 = H, Me) which were subjected to alkylation and sulfurization.
- Matiichuk,Potopnyk,Obushak
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experimental part
p. 1352 - 1361
(2009/09/06)
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- Synthesis, cannabinoid receptor affinity, and molecular modeling studies of substituted 1-aryl-5-(1H-pyrrol-1-yl)-1H-pyrazole-3-carboxamides
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The new 1-phenyl-5-(1H-pyrrol-1-yl)pyrazole-3-carboxamides were compared with the reference compounds AM251 and SR144528 for cannabinoid hCB1 and hCB2 receptor affinity. Compounds bearing 2,4-dichlorophenyl or 2,4-difluorophenyl groups at position 1 and 2,5-dimethylpyrrole moiety at position 5 of the pyrazole nucleus were generally more selective for hCB 1. On the other hand, the N-cyclohexyl group at the 3-carboxamide was the determinant for the hCB2 selectivity, in particular when a 3,4-dichlorophenyl group was also present at position 1. Compound 26 was the most selective ligand for the hCB1 receptor (Ki (CB 2)/Ki (CB1) = 140.7). Derivative 30, the most potent hCB1 ligand (Ki = 5.6 nM), was equipotent to AM251 and behaved as an inverse agonist in the cAMP assay (EC50 ~1 nM). The carbonyl oxygen of both 26 and 30 formed a H-bond with K3.28(192), while the substituents at the nitrogen fitted in a pocket formed by lipophilic residues. This H-bonding interaction was proposed to account for the high affinity for receptors' inactive state and the inverse agonist activity.
- Silvestri, Romano,Cascio, Maria Grazia,La Regina, Giuseppe,Piscitelli, Francesco,Lavecchia, Antonio,Brizzi, Antonella,Pasquini, Serena,Botta, Maurizio,Novellino, Ettore,Di Marzo, Vincenzo,Corelli, Federico
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p. 1560 - 1576
(2008/12/20)
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- Preparation of 4,5-dihydro-pyrazolo[3,4-c]pyrid-2-ones
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A novel process and intermediates thereof for making 4,5-dihydro-pyrazolo[3,4-c]pyrid-2-ones of the type shown below, as well as the corresponding pyrazoles, from appropriate phenyl hydrazines is described. These compounds can be useful as factor Xa inhib
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Page/Page column 20
(2010/10/20)
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- Derivatives of 4,6-diamino-1,2-dihydro-2-phenyl-1,2,4-triazolo[4,3-a] quinoxalin-2H-1-one: Potential antagonist ligands for imaging the A2A adenosine receptor by positron emission tomography (PET)
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The importance of the brain A2A adenosine receptor (A 2AAR) in movement disorders urges the development of radiolabeled ligands for imaging those receptors by positron emission tomography (PET). This study evaluated one class of Asu
- Holschbach, Marcus H.,Bier, Dirk,Wutz, Walter,Sihver, Wiebke,Schueller,Olsson, Ray A.
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p. 421 - 437
(2007/10/03)
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- N-(ALKOXYCARBONYLMETHYL)DIAZENE-N'-OXIDES AND SOME OF THEIR CONVERSIONS
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Upon reaction of aliphatic and aromatic nitroso compounds with esters of N,N-dibromoglycine N-substituted N'-(alkoxycarbonylmethyl)diazene-N-oxides are formed.The ethyl ester of (2-phenyldiazene-2-oxido)acetic acid in concentrated H2SO4 is transformed int
- Luk'yanov, O. A.,Salamonov, Yu. B.,Bass, A. G.,Strelenko, Yu. A.,Karpenko, N. F.
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p. 294 - 297
(2007/10/02)
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- Kinetics and mechanism of dehydrochlorination of N-aryl-C-ethoxycarbonylformohydrazidoyl chlorides
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The kinetics of triethylamine (TEA) catalyzed dehydrochlorination of a series of N-aryl-C-ethoxycarbonylformohydrazidoyl chlorides 1a-m have been studied under pseudo-first-order conditions in 4:1 (v/v) dioxane-water solution at 30 deg C.For all compounds
- Shawali, Ahmad S.,Albar, Hassan A.
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p. 871 - 875
(2007/10/02)
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- Synthesis and evaluation of furan, thiophene, and azole bis[(carbamoyloxy)methyl] derivatives as potential antineoplastic agents
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A series of bis(hydroxymethyl)-substituted heterocycles were synthesized and converted to the corresponding bis(methylcarbamate) derivatives. The heterocyclic systems studied were based on 2-phenyl-3-methylfuran, 1-phenylpyrazole, 1-phenyl-5-methylpyrazole, 1-phenyl-5-methylthiopene, 1-phenyl-1,2,3-triazole, 3-phenylisoxazole, 3-phenylisothiazole, 2-phenylthiazole, and 2-phenyloxazole. None of the bis(carbamates) prepared was active against murine P388 lymphocytic leukemia. Pyrrole bis(carbamate), which exhibited antileukemic activity, also showed reactivity toward 4-(p-nitrobenzyl)pyridine while the inactive bis(carbamates) were unreactive in the 4-(p-nitrobenzyl)pyridine assay.
- Anderson,Jones
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p. 1559 - 1565
(2007/10/02)
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