- Metabotropic glutamate receptor 5 negative allosteric modulators: Discovery of 2-chloro-4-[1-(4-fluorophenyl)-2,5-dimethyl-1 H-imidazol-4-ylethynyl]pyridine (basimglurant, RO4917523), a promising novel medicine for psychiatric diseases
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Negative allosteric modulators (NAMs) of metabotropic glutamate receptor 5 (mGlu5) have potential for the treatment of psychiatric diseases including depression, fragile X syndrome (FXS), anxiety, obsessive-compulsive disorders, and levodopa induced dyskinesia in Parkinson's disease. Herein we report the optimization of a weakly active screening hit 1 to the potent and selective compounds chloro-4-[1-(4-fluorophenyl)-2,5-dimethyl-1H-imidazol-4-ylethynyl]pyridine (basimglurant, 2) and 2-chloro-4-((2,5-dimethyl-1-(4-(trifluoromethoxy)phenyl)-1H-imidazol-4-yl)ethynyl)pyridine (CTEP, 3). Compound 2 is active in a broad range of anxiety tests reaching the same efficacy but at a 10- to 100-fold lower dose compared to diazepam and is characterized by favorable DMPK properties in rat and monkey as well as an excellent preclinical safety profile and is currently in phase II clinical studies for the treatment of depression and fragile X syndrome. Analogue 3 is the first reported mGlu5 NAM with a long half-life in rodents and is therefore an ideal tool compound for chronic studies in mice and rats.
- Jaeschke, Georg,Kolczewski, Sabine,Spooren, Will,Vieira, Eric,Bitter-Stoll, Nadia,Boissin, Patrick,Borroni, Edilio,Büttelmann, Bernd,Ceccarelli, Simona,Clemann, Nicole,David, Beatrice,Funk, Christoph,Guba, Wolfgang,Harrison, Anthony,Hartung, Thomas,Honer, Michael,Huwyler, J?rg,Kuratli, Martin,Niederhauser, Urs,P?hler, Axel,Peters, Jens-Uwe,Petersen, Ann,Prinssen, Eric,Ricci, Antonio,Rueher, Daniel,Rueher, Marianne,Schneider, Manfred,Spurr, Paul,Stoll, Theodor,T?nnler, Daniel,Wichmann, Jürgen,Porter, Richard H.,Wettstein, Joseph G.,Lindemann, Lothar
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Read Online
- Synthesis of a Precursor of the Antiviral Agent A-315675
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Ethyl 2-(acetylamino)-3-methoxy-3-methylhexanoate, a key precursor of the known pyrrolidine antiviral agent A-315675, was synthesized starting with the readily available acetoacetic ester.
- Egorov,Gimalova
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Read Online
- Synthesis of deuterium-labeled 2-quinoxalinecarboxylic acid and 3-methylquinoxaline-2-carboxylic acid from deuterium aniline
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An efficient and simple synthetic route of deuterium-labeled 2-quinoxalinecarboxylic acid-d4 (QCA-d4) and 3-methylquinoxaline-2-carboxylic acid-d4 (MQCA-d4) is presented with 99.9% and 99.6% isotopic enrichment using aniline-d5 as labeled starting material. Their chemical structures were confirmed by 1H NMR, and their isotopic abundance was determined by mass spectrometry analysis.
- Chen, Wulian,Zhao, Chaomin,Deng, Xiaojun
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Read Online
- Switching a Xanthine Oxidase Inhibitor to a Dual-Target Antagonist of P2Y1and P2Y12as an Oral Antiplatelet Agent with a Wider Therapeutic Window in Rats than Ticagrelor
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ADP-mediated platelet aggregation is signaled through G protein-coupled receptors P2Y1 and P2Y12 on the platelet. The clinical effectiveness of inhibiting P2Y12 has been well established, and preclinical studies indicated that the inhibition of P2Y1 could provide equivalent antithrombotic efficacy as P2Y12 antagonists and reduce bleeding risks. On the basis of the 2-phenyl-1H-imidazole scaffold of our previously reported xanthine oxidase inhibitor WSJ-557, we first achieved the transition from the xanthine oxidase inhibitors to dual-target antagonists against P2Y1 and P2Y12. We described the structure-activity relationships of the 2-phenyl-1H-imidazole compounds, which led to the identification of the most potent antiplatelet agents, 24w and 25w, both showing a rapid onset of action in pharmacokinetic study. Furthermore, the rat model suggested that 24w demonstrated a wider therapeutic window than ticagrelor, displaying equivalent and dose-dependent antithrombotic efficacy with lower blood loss compared to ticagrelor at same oral dose. These results supported that 24w and 25w could be promising drug candidates.
- Lei, Yu,Zhang, Bing,Liu, Dan,Zhao, Jian,Dai, Xiwen,Gao, Jun,Mao, Qing,Feng, Yao,Zhao, Jiaxing,Lin, Fengwei,Duan, Yulin,Zhang, Yan,Bao, Ziyang,Yang, Yuwei,Mou, Yanhua,Wang, Shaojie
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- Intracellular Distribution of Fluorescent Copper and Zinc Bis(thiosemicarbazonato) Complexes Measured with Fluorescence Lifetime Spectroscopy
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The intracellular distribution of fluorescently labeled copper and zinc bis(thiosemicarbazonato) complexes was investigated in M17 neuroblastoma cells and primary cortical neurons with a view to providing insights into the neuroprotective activity of a copper bis(thiosemicarbazonato) complex known as CuII(atsm). Time-resolved fluorescence measurements allowed the identification of the CuII and ZnII complexes as well as the free ligand inside the cells by virtue of the distinct fluorescence lifetime of each species. Confocal fluorescent microscopy of cells treated with the fluorescent copper(II)bis(thiosemicarbazonato) complex revealed significant fluorescence associated with cytoplasmic puncta that were identified to be lysosomes in primary cortical neurons and both lipid droplets and lysosomes in M17 neuroblastoma cells. Fluorescence lifetime imaging microscopy confirmed that the fluorescence signal emanating from the lipid droplets could be attributed to the copper(II) complex but also that some degree of loss of the metal ion led to diffuse cytosolic fluorescence that could be attributed to the metal-free ligand. The accumulation of the copper(II) complex in lipid droplets could be relevant to the neuroprotective activity of CuII(atsm) in models of amyotrophic lateral sclerosis and Parkinson's disease.
- Hickey, James L.,James, Janine L.,Henderson, Clare A.,Price, Katherine A.,Mot, Alexandra I.,Buncic, Gojko,Crouch, Peter J.,White, Jonathan M.,White, Anthony R.,Smith, Trevor A.,Donnelly, Paul S.
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- Oxidation of: O -dioxime by (diacetoxyiodo)benzene: Green and mild access to furoxans
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Furoxan has been widely used in the field of high energy density materials because of its excellent properties such as high density, high standard enthalpy of formation and high nitrogen content. However, its existing synthesis methods are still restricted by the problems of difficult substrate preparation and manual handling of hazardous reagents. Herein, we disclosed a mild oxidation strategy to efficiently obtain furoxan derivatives starting from readily available o-dioxime substrates. This reaction features high functional group tolerance and easy scale-up, and has excellent regioselectivity for specific nonsymmetric o-dioximes. This method greatly reduces the safety risk and simplifies the operation process, and means that diversified furoxan derivatives can be easily accessed, thus paving the way for the wide application of furoxan derivatives. This journal is
- He, Chunlin,Pang, Siping,Zhang, Qi,Zhang, Xun,Zhao, Cheng
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supporting information
p. 1489 - 1493
(2022/01/31)
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- From Synthetic Simplified Marine Metabolite Analogues to New Selective Allosteric Inhibitor of Aurora B Kinase
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Significant inhibition of Aurora B was achieved by the synthesis of simplified fragments of benzosceptrins and oroidin belonging to the marine pyrrole-2-aminoimidazoles metabolites isolated from sponges. Evaluation of kinase inhibition enabled the discovery of a synthetically accessible rigid acetylenic structural analogue EL-228 (1), whose structure could be optimized into the potent CJ2-150 (37). Here we present the synthesis of new inhibitors of Aurora B kinase, which is an important target for cancer therapy through mitosis regulation. The biologically oriented synthesis yielded several nanomolar inhibitors. The optimized compound CJ2-150 (37) showed a non-ATP competitive allosteric mode of action in a mixed-type inhibition for Aurora B kinase. Molecular docking identified a probable binding mode in the allosteric site "F"and highlighted the key interactions with the protein. We describe the improvement of the inhibitory potency and specificity of the novel scaffold as well as the characterization of the mechanism of action.
- Juillet, Charlotte,Ermolenko, Ludmila,Boyarskaya, Dina,Baratte, Blandine,Josselin, Béatrice,Nedev, Hristo,Bach, Stéphane,Iorga, Bogdan I.,Bignon, Jér?me,Ruchaud, Sandrine,Al-Mourabit, Ali
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p. 1197 - 1219
(2021/02/05)
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- Design, synthesis and biological evaluation of novel FXIa inhibitors with 2-phenyl-1H-imidazole-5-carboxamide moiety as P1 fragment
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Factor XIa, as a blood coagulation enzyme, amplifies the generation of the last enzyme thrombin in the blood coagulation cascade. It was proved that direct inhibition of factor XIa could reduce pathologic thrombus formation without an enhanced risk of bleeding. WSJ-557, a nonpurine imidazole-based xanthine oxidase inhibitor in our previous reports, could delay blood coagulation during its animal experiments, which prompted us to investigate its action mechanism. Subsequently, during the exploration of the action mechanism, it was found that WSJ-557 exhibited weak in vitro factor XIa binding affinity. Under the guide of molecular modeling, we adopted molecular hybridization strategy to develop novel factor XIa inhibitors with WSJ-557 as an initial compound. This led to the identification of the most potent compound 44g with a Ki value of 0.009 μM, which was close to that of BMS-724296 (Ki = 0.0015 μM). Additionally, serine protease selectivity study indicated that compound 44g display a desired selectivity, more 400-fold than those of thrombin, factor VIIa and factor Xa in coagulation cascade. Moreover, enzyme kinetics studies suggested that the representative compound 44g acted as a competitive-type inhibitor for FXIa, and molecular modeling revealed that it could tightly bind to the S1, S1′ and S2′ pockets of factor XIa. Furthermore, in vivo efficacy in the rabbit arteriovenous shunt model suggested that compound 44g demonstrated dose-dependent antithrombotic efficacy. Therefore, these results supported that compound 44g could be a potential and efficacious agent for the treatment of thrombotic diseases.
- Lei, Yu,Zhang, Bing,Zhang, Yan,Dai, Xiwen,Duan, Yulin,Mao, Qing,Gao, Jun,Yang, Yuwei,Bao, Ziyang,Fu, Xuefeng,Ping, Kunqi,Yan, Chengda,Mou, Yanhua,Wang, Shaojie
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- Lead optimization of a pyrrole-based dihydroorotate dehydrogenase inhibitor series for the treatment of malaria
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Malaria puts at risk nearly half the world's population and causes high mortality in sub-Saharan Africa, while drug resistance threatens current therapies. The pyrimidine biosynthetic enzyme dihydroorotate dehydrogenase (DHODH) is a validated target for malaria treatment based on our finding that triazolopyrimidine DSM265 (1) showed efficacy in clinical studies. Herein, we describe optimization of a pyrrole-based series identified using a target-based DHODH screen. Compounds with nanomolar potency versus Plasmodium DHODH and Plasmodium parasites were identified with good pharmacological properties. X-ray studies showed that the pyrroles bind an alternative enzyme conformation from 1 leading to improved species selectivity versus mammalian enzymes and equivalent activity on Plasmodium falciparum and Plasmodium vivax DHODH. The best lead DSM502 (37) showed in vivo efficacy at similar levels of blood exposure to 1, although metabolic stability was reduced. Overall, the pyrrole-based DHODH inhibitors provide an attractive alternative scaffold for the development of new antimalarial compounds.
- Kokkonda, Sreekanth,Deng, Xiaoyi,White, Karen L.,El Mazouni, Farah,White, John,Shackleford, David M.,Katneni, Kasiram,Chiu, Francis C. K.,Barker, Helena,Mclaren, Jenna,Crighton, Elly,Chen, Gong,Angulo-Barturen, Inigo,Jimenez-Diaz, Maria Belen,Ferrer, Santiago,Huertas-Valentin, Leticia,Martinez-Martinez, Maria Santos,Lafuente-Monasterio, Maria Jose,Chittimalla, Rajesh,Shahi, Shatrughan P.,Wittlin, Sergio,Waterson, David,Burrows, Jeremy N.,Matthews, Dave,Tomchick, Diana,Rathod, Pradipsinh K.,Palmer, Michael J.,Charman, Susan A.,Phillips, Margaret A.
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p. 4929 - 4956
(2020/06/08)
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- Sulfur-containing natural hinduchelins derivatives as potential antifungal agents against Rhizoctonia solani
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Aryl-oxazole alkaloids are an important class of heterocyclic natural products, and which has been demonstrated to exhibit broad biological functions. During the course of our research for highly active compounds from natural products, the natural hinduchelins A-D with typical aryl-oxazole unit have been synthesized and investigated. So, in order to develop highly potential functional molecules, a series of novel sulfur-containing aryl-oxazole compounds derived from natural hinduchelins was designed and synthesized, and their in vitro fungicidal activities against four common plant pathogenic fungi (oomycetes Phytophthora capsici, ascomycetes Sclerotinia sclerotiorum, deuteromycetes Botrytis cinerea and basidiomycetes Rhizoctonia solani) were evaluated, the results demonstrated that compounds 7b and 7c displayed good selectivity and specificity in vitro against basidiomycetes R. solani. In addition, the in vivo antifungal activities also indicated compounds 7b and 7c can protect the horsebean against infection by R. solani, and the possible mechanism of antifungal action for these compounds has also been investigated.
- Cao, Chunxia,Fang, Wei,Huang, Daye,Huang, Wenbo,Ke, Shaoyong,Shi, Liqiao,Wan, Zhongyi,Wang, Kaimei,Zhang, Zhigang
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- Stable isotope labeled 3-methyl-quinoxaline-2-carboxylic acid and synthesis method thereof
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The invention discloses a stable isotope labeled 3-methyl-quinoxaline-2-carboxylic acid and a synthesis method thereof. The synthesis method comprises the following steps: S1, acetoacetate reacts withnitrite under the catalysis of organic acid to obtain 2-hydroxyimino-acetoacetate; s2, condensing the 2-hydroxyimino-acetoacetate with stable isotope labeled aniline under the catalysis of acetic acid, and then adding phosphorus oxychloride to react to obtain isotope labeled 3-methyl-quinoxaline-2-carboxylate; s3, hydrolyzing the stable isotope labeled 3-methyl-quinoxaline-2-carboxylic acid esterunder alkaline conditions, adjusting the pH value to acidity after the reaction is finished, and precipitating the stable isotope labeled 3-methyl-quinoxaline-2-carboxylic acid from the aqueous solution. The synthesis method not only has low preparation cost and few experimental steps, but also has purity and isotope abundance of more than 98%, and can be completely used as an internal standard for detecting 3-methyl-quinoxaline-2-carboxylic acid, thus greatly reducing detection cost.
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Paragraph 0027; 0028
(2019/10/01)
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- OXADIAZOLE TRANSIENT RECEPTOR POTENTIAL CHANNEL INHIBITORS
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The invention relates to compounds of formula I: and pharmaceutically acceptable salts thereof wherein A, X, R1, R4 and n are as defined herein. In addition, the present invention relates to methods of manufacturing and methods of using the compounds of formula I as well as pharmaceutical compositions containing such compounds. The compounds may be useful in treating diseases and conditions mediated by TRPA1, such as pain.
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- An efficient synthesis and bioactivity evaluation of oxazole-containing natural hinduchelins A-D and their derivatives
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Oxazoles are an important class of biologically active metabolites from nature, and exhibit broad biological activities as the lead for drug discovery. Hinduchelins are a class of unusual natural products with an oxazole unit, isolated from Streptoalloteichus hindustanus, and with a potential iron-chelating ability. These compounds are the first identified naturally occurring unusual oxazole derivatives to possess a catechol unit. However, some of these compounds are not abundant in nature, and thus, the efficient syntheses of these compounds are advantageous in exploring their potential applications. This paper reports the efficient synthesis and bio-evaluation of hinduchelins A-D and their derivatives with convenient procedures and high yields.
- Ke, Shaoyong,Zhang, Zhigang,Shi, Liqiao,Liu, Manli,Fang, Wei,Zhang, Yani,Wu, Zhaoyuan,Wan, Zhongyi,Long, Tong,Wang, Kaimei
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supporting information
p. 3635 - 3639
(2019/04/14)
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- Synthesis technology of 2,5-dihydroxymethyl-3,6-dimethylpyrazine
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The invention discloses a synthesis technology of 2,5-dihydroxymethyl-3,6-dimethylpyrazine (liguzinediol). According to the method, ethyl acetoacetate which is used as a raw material undergoes a nitrosation reaction to generate 2-hydroximinoethyl acetoacetate; through palladium-carbon catalytic reduction, condensation and aromatization, 3,6-dimethylpyrazine-2,5-dicarboxylic acid diethyl ester is generated; and finally through reduction, liguzinediol is obtained. The technology has advantages as follows: raw materials are easily available; reaction is mild; operation is simple; separation and purification are easy; and cost is low. The technology is suitable for industrial production.
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Paragraph 0029; 0036; 0043; 0050; 0057; 0064
(2018/05/16)
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- OXADIAZOLONES AS TRANSIENT RECEPTOR POTENTIAL CHANNEL INHIBITORS
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The invention relates to compounds of formula (I) and pharmaceutically acceptable salts thereof. In addition, the present invention relates to methods of manufacturing and methods of using the compounds of formula (I) as well as pharmaceutical compositions containing such compounds. The compounds may be useful in treating diseases and conditions mediated by TRPA1, such as pain.
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Paragraph 0269-0272
(2018/06/12)
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- A phosphine-mediated synthesis of 2,3,4,5-tetra-substituted N-hydroxypyrroles from α-oximino ketones and dialkyl acetylenedicarboxylates under ionic liquid green-media
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Background: The development of multicomponent reactions (MCRs) in the presence of task-specific ionic liquids (ILs), used not only as environmentally benign reaction media, but also as catalysts, is a new approach that meet with the requirements of sustainable chemistry. In recent years, the use of ionic liquids as a green media for organic synthesis has become a chief study area. This is due to their unique properties such as non-volatility, non-flammability, chemical and thermal stability, immiscibility with both organic compounds and water and recyclability. Ionic liquids are used as environmentally friendly solvents instead of hazardous organic solvents. Objective: We report the condensation reaction between α-oximinoketone and dialkyl acetylene dicarboxylate in the presence of triphenylphosphine to afford substituted pyrroles under ionic liquid conditions in good yields. Result: Densely functionalized pyrroles was easily prepared from reaction of α-oximinoketones, dialkyl acetylene dicarboxylate in the presence of triphenylphosphine in a quantitative yield under ionic liquid conditions at room temperature. Conclusion: In conclusion, ionic liquids are indicated as a useful and novel reaction medium for the selective synthesis of functionalized pyrroles. This reaction medium can replace the use of hazardous organic solvents. Easy work-up, synthesis of polyfunctional compounds, decreased reaction time, having easily available-recyclable ionic liquids, and good to high yields are advantages of present method.
- Shahvelayati, Ashraf S.,Ghazvini, Maryam,Yadollahzadeh, Khadijeh,Delbari, Akram S.
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- Tandem C-N Bond Formation through Condensation and Metal-Free N-Arylation: Protocol for Synthesizing Diverse Functionalized Quinoxalines
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Diverse functionalized quinoxalines were synthesized in good yields from arylamines and readily available β-keto oximes through condensation and metal-free N-arylation. The reaction was compatible with various functional groups, such as halides, cyano, and esters. A mechanism was proposed based on the experimental results. These quinoxalines were easily obtained on a gram scale and converted to various useful scaffolds. Compound LASSBio-1022 was prepared in 83% yield in two steps.
- Jiao, Yan-Xiao,Wu, Ling-Ling,Zhu, Hai-Miao,Qin, Jiang-Ke,Pan, Cheng-Xue,Mo, Dong-Liang,Su, Gui-Fa
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p. 4407 - 4414
(2017/04/28)
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- Rhodium-catalyzed asymmetric hydrogenation of tetrasubstituted β-acetoxy-α-enamido esters and efficient synthesis of droxidopa
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A rhodium-catalyzed asymmetric hydrogenation of challenging tetrasubstituted β-acetoxy-α-enamido esters was developed, giving chiral β-acetoxy-α-amido esters in high yields with excellent enantioselectivities (up to >99% ee). The products could be easily transformed to β-hydroxy-α-amino acid derivatives which are valuable chiral building blocks and a novel route for the synthesis of droxidopa was also developed.
- Guan, Yu-Qing,Gao, Min,Deng, Xu,Lv, Hui,Zhang, Xumu
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supporting information
p. 8136 - 8139
(2017/07/24)
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- Method for synthesizing ethyl 2-(2-aminothiazole-4-yl)-2-hydroxyiminoacetate
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The invention relates to a method for synthesizing ethyl 2-(2-aminothiazole-4-yl)-2-hydroxyiminoacetate, and belongs to the technical field of the preparation of antibiotic drug intermediates. The method provided by the invention comprises the following steps: using ethyl acetoacetate, sodium nitrite and concentrated sulfuric acid as raw materials; using purified water as a solvent; performing oximation reaction first, and then performing halogenation reaction; then adding thiourea; using 12-ammonium phosphomolybdate (AMP) as the catalyst, and using methanol as a solvent to perform cyclization reaction, thereby obtaining ethyl2-(2-aminothiazole-4-yl)-2-hydroxyiminoacetate. The method provided by the invention is simple in process, shortens the reaction cycle, increases the reaction yield, and reduces corrosion to equipment; the used catalyst is separated from the product easily and can be reused, thereby reducing the production cost, greatly reducing the 'three wastes' pollution, and having an extremely high industrial application value.
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Paragraph 0011; 0031; 0032; 0038; 0039; 0045; 0046
(2017/07/21)
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- Nonpeptidic Selective Inhibitors of the Chymotrypsin-Like (β5 i) Subunit of the Immunoproteasome
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Elevated expression of the immunoproteasome has been associated with autoimmune diseases, inflammatory diseases, and various types of cancer. Selective inhibitors of the immunoproteasome are not only scarce, but also almost entirely restricted to peptide-based compounds. Herein, we describe nonpeptidic reversible inhibitors that selectively block the chymotrypsin-like (β5i) subunit of the human immunoproteasome in the low micromolar range. The most potent of the reversibly acting compounds were then converted into covalent, irreversible, nonpeptidic inhibitors that retained selectivity for the β5i subunit. In addition, these inhibitors discriminate between the immunoproteasome and the constitutive proteasome in cell-based assays. Along with their lack of cytotoxicity, these data point to these nonpeptidic compounds being suitable for further investigation as β5i-selective probes for possible application in noncancer diseases related to the immunoproteasome.
- Sosi?, Izidor,Gobec, Martina,Brus, Boris,Knez, Damijan,?ivec, Matej,Konc, Janez,Le?nik, Samo,Ogrizek, Mitja,Obreza, Ale?,?igon, Du?an,Jane?i?, Du?anka,Mlinari?-Ra??an, Irena,Gobec, Stanislav
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supporting information
p. 5745 - 5748
(2016/05/09)
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- HETEROCYCLICALLY SUBSTITUTED TRIFLUOROMETHYLPYRIMIDINONES AND THEIR USE
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The present application relates to novel heterocyclically substituted 6-(trifluoromethyl)pyrimidin-4(3H)-one derivatives, to processes for their preparation, to their use alone or in combinations for the treatment and/or prevention of diseases, and to their use for preparing medicaments for the treatment and/or prevention of diseases, in particular for treatment and/or prevention of cardiovascular, renal, inflammatory and fibrotic diseases.
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Paragraph 0212
(2017/02/24)
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- Nano-K2CO3: Preparation, characterization and evaluation of reactive activities
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A novel base, nano-K2CO3, was easily prepared by ultrafine wet milling. The surface properties and the reactive activities of nano-K2CO3 were characterized. It was found that such a base showed higher basicity than normal K2CO3 and could replace sodium (or potassium) alkoxide to carry out monoalkylation and oximation of active methylene compounds. The nano-K2CO3 could be regenarated and reused 10 times without loss of its reactive activity.
- Li, Jun-Zhang,Fan, Shi-Ming,Sun, Xuan-Fei,Liu, Shouxin
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p. 1865 - 1869
(2016/01/20)
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- PSORALEN DERIVATIVES AS NON-PEPTIDIC INHIBITORS OF CHYMOTRYPSIN-LIKE ACTIVITY OF THE IMMUNOPROTEASOME
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This invention relates to new inhibitors of chymothrypsin-like activity of the immunoproteasome (inhibitors of β5? or LMP7 subunit) with the general formula (I), where substituents are described in patent description. Compounds can be in the form of pure enantiomers or as racemic mixtures, or in the form of pharmaceutically acceptable salts. The present invention relates to the use of these inhibitors for the treatment of diseases where immunoproteasome activity is increased.
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Paragraph 0167
(2016/10/11)
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- HETEROCYCLIC SUBSTITUTED TRIFLUOROMETHYL PYRIMIDINONES AND THEIR USE
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The present application relates to novel heterocyclically substituted 6-(trifluoromethyl)pyrimidin-4(3H)-one derivatives, to processes for their preparation, to their use alone or in combinations for the treatment and/or prevention of diseases, and to their use for preparing medicaments for the treatment and/or prevention of diseases, in particular for treatment and/or prevention of cardiovascular, renal, inflammatory and fibrotic diseases.
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Paragraph 0512
(2016/10/04)
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- Phenyl oxazole compound and in the preparation of medicine for the treatment of cancer the application of the
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The invention provides two novel phenyloxazole compounds and application thereof to a medicament for preventing and treating cancers and further provides a preparation method of the two compounds. The two compounds provided by the invention can achieve effects of preventing and treating the cancers such as the cervical cancer, the colon cancer, the liver cancer and the breast cancer by inhibiting expression of a microRNA-21 cancer factor and inhibiting growth and migration of cancer cells. Meanwhile, a micromolecule medicament used by the invention is easy to obtain, low in price, stable in performance and convenient to store and transport.
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Paragraph 0013; 0039-0041
(2017/05/05)
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- Site-selective solid phase synthesis of carbonylated peptides
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Abstract The aim of our research was to design an efficient method for the solid phase synthesis of carbonylated peptides. For this purpose, we designed and synthesized a fully protected derivative Fmoc-amino(2,5,5-trimetyhyl-1,3-dioxolan-2-yl)acetic acid
- Waliczek, Mateusz,Kijewska, Monika,Stefanowicz, Piotr,Szewczuk, Zbigniew
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p. 1353 - 1365
(2015/06/16)
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- Synthesis and evaluation of 1-hydroxy/methoxy-4-methyl-2-phenyl-1 H-imidazole-5-carboxylic acid derivatives as non-purine xanthine oxidase inhibitors
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Xanthine oxidase is a key enzyme that catalyses hypoxanthine and xanthine to uric acid, whose overproduction leads to the gout-causing hyperuricemia. In this study, a series of 1-hydroxy/methoxy-4-methyl-2-phenyl-1H-imidazole-5-carboxylic acid derivatives (4ae4k and 6ae6k) was synthesized and evaluated for their inhibitory potency against xanthine oxidase. The 1-hydroxyl substituted derivatives 4ae4k showed excellent inhibitory potency with IC50 values ranging from 0.003 μM to 1.2 μM, with compounds 4d (IC50= 0.003 μM), 4e (IC50 = 0.003 μM), and 4f (IC50 = 0.006 μM) manifesting the most potent xanthine oxidase inhibitory potency that were comparable with that of Febuxostat (IC50 = 0.01 μM). LineweavereBurk plot analysis revealed that representative compound 4f acted as a mixed-type inhibitor for xanthine oxidase. The basis of significant inhibition of xanthine oxidase by 4f was rationalized by its molecular docking into the active site of xanthine dehydrogenase.
- Chen, Shaolei,Zhang, Tingjian,Wang, Jian,Wang, Fangyang,Niu, Handong,Wu, Chunfu,Wang, Shaojie
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p. 343 - 353
(2015/09/22)
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- Fosmidomycin analogues with N-hydroxyimidazole and N-hydroxyimidazolone as a chelating unit
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Fosmidomycin has been reported to have many biological activities as an antibacterial and antimalarial, along with being a herbicidal agent. Its unique mode of action involves the inhibition of a key step of the non mevalonate pathway by blockade of a crucial enzyme, the 1-deoxy-d-xylulose 5-phosphate reductoisomerase (DXR), whose expression is present in bacteria, plasmodium parasites and higher plants, but not in mammals. Herein we report the development of fosmidomycin and of FR-900098 constrained analogues belonging to an unusual heterocyclic based complexing subunit involving N-hydroxyimidazoles and cyclic N-hydroxyureas.
- Midrier, Camille,Montel, Sonia,Braun, Ralf,Haaf, Klaus,Willms, Lothar,Van Der Lee, Arie,Volle, Jean-Noel,Pirat, Jean-Luc,Virieux, David
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p. 23770 - 23778
(2014/07/07)
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- Synthesis and study of prototropic tautomerism of 2-(3-chromenyl)-1- hydroxyimidazoles
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A series of novel derivatives of imidazole containing a chromenyl moiety in position 2 of the ring has been synthesized. A characteristic response of the chromenyl ring H-2 proton to its environment allows the study of the prototropic tautomerism of novel 1-hydroxyimidazoles in solution using 1H NMR spectroscopy. It has been shown that the predominance of one or another tautomer depends on the nature of the substituents of the imidazole ring, and the proton-donating/proton-withdrawing properties of a solvent. X-ray diffraction data for two of the compounds has revealed that in the solid state these 1-hydroxyimidazole derivatives exist as N-oxide tautomers.
- Nikitina, Polina A.,Kuz'Mina, Ludmila G.,Perevalov, Valery P.,Tkach, Iosif I.
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p. 3249 - 3256
(2013/05/09)
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- Iodine(III)-Mediated [3 + 2] cyclization for one-pot synthesis of benzo[ d ]isoxazole-4,7-diols in aqueous medium
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A one-pot [3 + 2] cycloadditive synthesis of benzo[d]isoxazole-4,7-diols in aqueous medium was carried out via nitrile oxides and benzoquinone intermediates by taking advantage of iodobenzene diacetate as an oxidant. This method can also be used to synthesize benzodiisoxazole-4,8-diols, isoxazolo[5,4-a]phenazines, and indazole-4,7-diols, which are difficult to obtain by classical methods.
- Hou, Yingwei,Lu, Shichao,Liu, Gang
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p. 8386 - 8395
(2013/09/24)
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- Synthesis and structure-activity relationships of novel zwitterionic compounds as peroxisome proliferator activated receptor α/γ dual agonists with improved physicochemical properties
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We describe herein the design, syntheses and structure-activity relationships (SAR) of novel zwitter-ionic compounds as non-thiazolidinedion (TZD) based peroxisome proliferator activated receptor (PPAR) α/γ dual agonists. In the previous report, we obtained compound 1 showing potent PPARα/γ dual agonistic activities, together with a great glucose lowering effect in the db/db mice. However, this compound possessed fatal issues such as potent cytochrome P450 (CYP)3A4 direct inhibitory activity. Thus, we carried out the medicinal optimization to improve these while maintaining the potent PPAR agonistic activity. As a result, the issues were addressed by changing the furan ring to a low lipophilic 1,3,4-oxadiazole ring. Additionally, these oxadiazole derivatives exhibited a significant decrease in plasma glucose and plasma triglyceride levels without marked weight gain.
- Shibata, Yoshihiro,Kagechika, Katsuji,Yamaguchi, Mitsuhiro,Yoshikawa, Kenji,Chiba, Kiyoshi,Takano, Hiromichi,Akiyama, Chiyuki,Ono, Mayumi,Nishi, Mina,Kubo, Hideo,Kobayashi, Yoshimasa,Usui, Hiroyuki
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p. 1248 - 1263
(2014/01/06)
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- AROMATIC HETEROCYCLIC DERIVATIVE HAVING TRPV4-INHIBITING ACTIVITY
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A compound having TRPV4 inhibitory activity or a pharmaceutically acceptable salt thereof is provided. The present invention is related to a compound represented by the formula (I). wherein R1a is substituted or unsubstituted alkyl or the like;
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Page/Page column 84
(2012/11/07)
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- Synthesis and anticonvulsant activity of some new series of pyrrole derivatives
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A new series of compounds 3a-f were synthesized from condensation method. Newly synthesized compounds were established by IR, 1H NMR, 13C NMR, mass spectral and elemental analysis. Synthesized compounds 3a-f were screened for anticonvulsant activity. The
- Idhayadhulla,Kumar, R. Surendra,Nasser, A. Jamal Abdul,Kavimani,Indumathy
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p. 3699 - 3708
(2013/03/13)
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- A rapid synthesis of quinoxalines starting from ketones
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A fast and general synthesis of quinoxalines, performed in two stages or as a one-pot reaction, starting from ketones via their α-hydroxylimino ketone derivatives, and condensation of the latter with 1,2-diaminobenzene under microwave irradiation, is described.
- Padmavathy,Nagendrappa, Gopalpur,Geetha
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experimental part
p. 544 - 547
(2011/03/18)
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- NOVEL ARYLPIPERAZINE-CONTAINING IMIDAZOLE 4-CARBOXAMIDE DERIVATIVES AND PHARMACEUTICAL COMPOSITION COMPRISING SAME
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A novel arylpiperazine-containing imidazole 4-carboxamide derivative or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition comprising the same as an active ingredient for preventing or treating a depressive disorder are provided.
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Page/Page column 31; 47
(2011/02/24)
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- NOVEL FUSED PYRIDAZINE DERIVATIVES
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The present invention relates to novel fused pyridazine compounds, their pharmaceutically acceptable salts, and their isomers, stereoisomers, conformers, tautomers, polymorphs, hydrates and solvates. The present invention also encompasses pharmaceutically acceptable compositions of said compounds and process for preparing novel compounds. The invention further relates to the use of the above-mentioned compounds for the preparation of medicament for use as pharmaceuticals.
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Page/Page column 66-67
(2011/05/06)
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- Straightforward access to (imidazol-2-yl)acetates by reaction of 2-unsubstituted imidazole 3-oxides with dimethyl acetylenedicarboxylate
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A new method for the preparation of 1,4,5-trisubstituted (imidazol-2-yl)acetates, based on the reaction of the corresponding imidazole 3-oxides with dimethyl acetylenedicarboxylate (DMAD) is described. Formation of the products is rationalized by a formal 1,3-dipolar cycloaddition and subsequent oxaloyl cleavage. 1,4,5-Trisubstituted imidazole 3-oxides bearing an electron-withdrawing substituent at C(4), easily react with dimethyl acetylenedicarboxylate (DMAD), yielding the corresponding oxobutanoates, which subsequently, in a one-pot procedure undergo hydrolysis through an "oxaloyl cleavage" mode. New (imidazol-2-yl)acetates were isolated in high yields. Copyright
- Mlostoń, Grzegorz,Jasiński, Marcin,Heimgartner, Heinz
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scheme or table
p. 2542 - 2547
(2011/05/16)
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- Design and synthesis of novel arylpiperazine derivatives containing the imidazole core targeting 5-HT2A receptor and 5-HT transporter
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Serotonin antagonist reuptake inhibitor (SARI) drugs that block both 5-HT2 receptors and the serotonin transporters have been developed. The human 5-HT2A/2C receptor has been implicated in several neurological conditions, and potent
- Seo, Hee Jeong,Park, Eun-Jung,Kim, Min Ju,Kang, Suk Youn,Lee, Suk Ho,Kim, Hyun Jung,Lee, Ki Nam,Jung, Myung Eun,Lee, Minwoo,Kim, Mi-Soon,Son, Eun-Jung,Park, Woo-Kyu,Kim, Jeongmin,Lee, Jinhwa
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experimental part
p. 6305 - 6318
(2011/11/06)
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- A cyclic porphyrin trimer as a receptor for fullerenes
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(Equation Presented). A cyclic porphyrin trimer has been synthesized which has a high affinity for fullerenes. It forms 1:1 complexes with C60 and C70 with association constants of 2×106 and 2×108 M-1, respectively, in toluene. Its affinities for C86 and La@C82 are too strong to measure by fluorescence titration. The solvent dependence of the association constants shows that solvation of both the guest and the host influence the binding strength.
- Gil-Ramirez, Guzman,Karlen, Steven D.,Shundo, Atsuomi,Porfyrakis, Kyriakos,Ito, Yasuhiro,Briggs, G. Andrew D.,Morton, John J. L.,Anderson, Harry L.
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supporting information; experimental part
p. 3544 - 3547
(2010/10/02)
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- Efficient synthesis of an A-B-C-tricycle fragment for a structural model of tolyporphin
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An efficient stereocontrolled synthesis of an A-B-C-tricycle fragment 7 for a structural model of tolyporphin 3 is described. All the rings were prepared from readily available starting materials. One of the two key steps is a selective ring-opening reaction of the lactone cycle in bicyclolactam-lactone 17 to cyanopyrrolidone 18, which introduces the chirality into synthetic compounds. The other key step is the combination of A ring with B-C-bicycle via a two-time Eschenmoser sulfide contraction. A-B-C-tricycle fragment 7 allows a new approach toward tolypophin compounds and other uroporphinoids.
- Hu, Bing C.,Zhou, Wei Y.,Liu, Zu L.,Cai, Chao J.,Xu, Shi C.
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experimental part
p. 89 - 100
(2010/11/18)
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- Synthesis and selected transformations of 3-oxido-1H-imidazole-4- carboxamides
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An efficient synthesis of new N-alkyl- and N-aryl-3-oxido-1H-imidazole-4- carboxamides based on exploration of inexpensive, commercially available ethyl acetoacetate, paraformaldehyde and primary amines is described. Representative compounds were tested in selected transformations, such as 'sulfur-transfer reaction' leading to imidazole-2-thiones and isomerization to corresponding imidazol-2-ones. Strong intramolecular hydrogen bonding via the N-oxide function results in the reduced reactivity of 3-oxido-1H-imidazole-4-carboxamides in both reactions. Moreover, the palladium catalyzed C(2)-arylation of imidazole ring as well as azide-alkyne [3+2] cycloaddition using the N-propargyl substituted 4-carboxamide derived from an imidazole 3-oxide as a dipolarophile, were also studied.
- Mloston, Grzegorz,Jasinski, Marcin
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scheme or table
p. 871 - 885
(2011/05/19)
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- Synthesis and spectral properties of new 3,3'-bis(dipyrrolylmethene) with acetylene spacer
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Bis(2,4,7,9-tetramethyl-8-ethyldipyrrolylmethen-3-yl)acetylene dihydrobromide (H2L·2HBr), new bis(dipyrrolylmethene), in whose molecule dipyrrolylmethene domains were connected through 3,3'-carbon atoms of internal pyrrole nuclei by acetylene spacer, were synthesized by original procedure. The compound was characterized by element analysis, IR, 1H NMR, and electronic spectroscopy. The comparative analysis of spectral properties shows the reduction of the basicity of H2L ligand in comparison with the structural analogs, which contain internal methylene spacer. The quantum-chemical simulation showed that the rigid acetylene spacer gives linear structure to the H2L molecule in contrast to the spiral-shaped geometry of structural analogs with-CH2-spacer. Pleiades Publishing, Ltd., 2010.
- Antina,Guseva,Loginova,Semeikin,V'Yugin
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experimental part
p. 2374 - 2381
(2011/04/14)
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- Unusual domino Michael/aldol condensation reactions employing oximes as N-selective nucleophiles: Synthesis of N-hydroxypyrroles
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(Figure Presented) A facile synthesis of N-hydroxypyrroles has been developed using readily available α-carbonyl oximes and α,β-unsaturated aldehydes. The domino reaction proceeds through iminium activation of α,β-unsaturated aldehydes, Michael addition u
- Tan, Bin,Shi, Zugui,Chua, Pei Juan,Li, Yongxin,Zhong, Guofu
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supporting information; experimental part
p. 758 - 761
(2009/05/06)
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- Synthesis and selected transformations of 1H-imidazole 3-oxides derived from amino acid esters
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A series of new optically active 1H-imidazole 3-oxides 5 with a substituted acetate group at N(1) as the chiral unit were prepared by the reaction of α-(hydroxyimino) ketones, α-amino acid methyl esters, and formaldehyde. In an analogous reaction, ethyl 2
- Jasinski, Marcin,Mloston, Grzegorz,Linden, Anthony,Heimgartner, Heinz
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experimental part
p. 1916 - 1933
(2009/02/07)
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- Design, synthesis and X-ray structure of protein-ligand complexes: Important insight into selectivity of memapsin 2 (β-secretase) inhibitors
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Structure-based design, synthesis, and X-ray structure of protein-ligand complexes of memapsin 2 are described. The inhibitors are designed specifically to interact with S2- and S3-active site residues to provide selectivity over mem
- Ghosti, Arun K.,Kumaragurubaran, Nagaswamy,Hong, Lin,Lei, Hui,Hussain, Khaja Azhar,Liu, Chun-Feng,Devasamudram, Thippeswamy,Weerasena, Vajira,Turner, Robert,Koelsch, Gerald,Bilcer, Geoffrey,Tang, Jordan
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p. 5310 - 5311
(2007/10/03)
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- PREPARATION OF 4,5-DIALKYL-3-ACYL-PYRROLE-2-CARBOXYLIC ACID DERIVATIVES BY FISCHER-FINK TYPE SYNTHESIS AND SUBSEQUENT ACYLATION
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The present invention relates to an improved synthesis of pyrrole capping group precursors of formula I-a: comprising: combining an aqueous solution of the compound of formula IV-a: wherein R3 is C1-12 aliphatic, C3-12 alkyl-cycloaliphatic, C3-12 alkyl-aryl, C3-12 alkyl-heteroaryl, or C3-12 alkyl-cycloaliphatic; with a compound of formula V-a, wherein R1 and R2 are each independently C1-6 aliphatic; in the presence of zinc, water, and optionally an additional suitable solvent to form a compound of formula VI.
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Page/Page column 16-19
(2008/06/13)
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- Synthesis of 2,4,5-Trisubstituted Oxazoles
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2,4,5-Trisubstituted oxazoles were synthesized in good yields starting from α-methylene ketones by nitrosation, condensation with aldehydes and reduction with zinc in acetic acid at 40 deg C. (5-Methyl-2-phenyloxazol-4-yl)ethanol was prepared by reduction of ethyl (5-methyl-2-phenyloxazol-4-yl)acetate with LiAlH4.
- Cai, Xiao-hua,Yang, Hai-jun,Zhang, Guo-lin
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p. 1569 - 1571
(2007/10/03)
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- PYRIDIN-4-YL-ETHYNYL-IMIDAZOLES AND PYRAZOLES AS MGLU5 RECEPTOR ANTAGONISTS
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The present invention relates to diazole derivatives of the general formula (I) wherein A, E, R1, Wand R3 are as defined in the claims and description, their use for the preparation of medicaments for treating diseases and processes
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Page/Page column 40
(2008/06/13)
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- Inhibitors of serine proteases, particularly HCV NS3-NS4A protease
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The present invention relates to compounds that inhibit serine protease activity, particularly the activity of hepatitis C virus NS3-NS4A protease. As such, they act by interfering with the life cycle of the hepatitis C virus and are also useful as antivi
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