- Novel potent benzimidazole-based microsomal prostaglandin E2 synthase-1 (mPGES-1) inhibitors derived from BRP-201 that also inhibit leukotriene C4 synthase
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Microsomal prostaglandin E2 synthase-1 (mPGES-1) is recognized as a promising therapeutic target for next-generation anti-inflammatory drugs to treat inflammatory diseases. In this study, we report the identification of new, potent and selectiv
- Banoglu, Erden,Jordan, Paul M.,Kretzer, Christian,Werz, Oliver,?al??kan, Burcu,Ergül, Azize Gizem,Maz, Tu??e Gür,Ol?a?, Abdurrahman
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- Design, synthesis and biological activity evaluation of novel methyl substituted benzimidazole derivatives
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Ten new dabigatran derivatives (7a–j) with high docking scoring were designed, synthesised and biologically evaluated. The inhibitory in vitro activity of these compounds on thrombin was evaluated on the basis of preliminary activity screening results. The IC50 values of compounds 7a, 7d and 7j were 1.92, 2.17 and 1.54 nM, respectively, and are equivalent to the dabigatran (IC50 = 1.20 nM). Therefore, the most active compound, 7j, was selected to further investigate the anticoagulant activity in rats. Compound 7j presented excellent in vivo inhibitory effects on arteriovenous thrombosis, and the inhibition rate was (84.19 ± 1.14) %. The anticoagulant activity of compound 7k synthesised in the previous work was evaluated in vivo, and its inhibition rate was (85.58 ± 2.89) %. This rate was nearly equivalent to that of dabigatran (85.07 ± 0.61) %. Results indicated that compounds 7a, 7d, 7j and 7k can be further studied as novel antithrombin drug candidates.
- Liu, Qianqian,Ren, Yujie,Zhang, Tianrong
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- Computer-aid drug design, synthesis, and anticoagulant activity evaluation of novel dabigatran derivatives as thrombin inhibitors
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In this study, computer-aided drug design techniques were adopted to explore the structural and chemical features for dabigatran and design novel derivatives. The built 3D-QSAR models demonstrated significant statistical quality and excellent predictive ability by internal and external validation. Based on QSAR information, 11 novel dabigatran derivatives (12a–12k) were designed and predicted, then ADME prediction and molecular docking were performed. Furthermore, all designed compounds were synthesized and characterized by 1H NMR, 13C NMR and HR-MS. Finally, they were evaluated for anticoagulant activity in vitro. The activity results showed that the 10 obtained compounds exhibited comparable activity to the reference dabigatran (IC50 = 9.99 ± 1.48 nM), except for compound 12i. Further analysis on molecular docking was performed on three compounds (12a, 12c and 12g) with better activity (IC50 = 11.19 ± 1.70 nM, IC50 = 10.94 ± 1.85 nM and IC50 = 11.19 ± 1.70 nM). MD simulations (10 ns) were carried out, and their binding free energies were calculated, which showed strong hydrogen bond and pi–pi stacking interactions with key residues Gly219, Asp189 and Trp60D. The 10 novel dabigatran derivatives obtained can be further studied as anticoagulant candidate compounds.
- Huang, Shanshan,Ren,Peng, Xiuxiu,Qian, Pingping,Meng, Lingwei
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- Benzimidazole derivative and pharmaceutical purposes thereof
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The invention discloses a benzimidazole derivative and pharmaceutical purposes thereof, and particularly discloses a benzimidazole derivative shown in a formula I and purposes of the benzimidazole derivative to preparation of drugs for treating and/or pre
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Paragraph 0080-0082; 0083
(2019/10/29)
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- Synthesis, Crystal Structure, and Anti-Gastric Cancer Activity of Ethyl 3-(3-Amino-4-(Methylamino)-N-(Pyridin-2-Yl) Benzamido)Propanoate
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A new heterocyclic compound ethyl 3-(3-amino-4-(methylamino)-N-(pyridin-2-yl)benzamido)propanoate (1), designed using 4-(methylamino)-3-nitrobenzoic acid (2) as a starting material is successfully obtained via a multiple synthesis route and finally characterized by IR, 1H NMR, and single crystal X-ray crystallography. In addition, the in vitro anti-cancer activity of newly synthesized complex 1 is emulated against three human gastric cancer cell lines SGC-790, MKN-4, and MKN45.
- Liu,Peng,Yue,Li,Zhang
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p. 2009 - 2014
(2020/01/11)
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- Molecular modeling studies, synthesis and biological evaluation of dabigatran analogues as thrombin inhibitors
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In this work, 48 thrombin inhibitors based on the structural scaffold of dabigatran were analyzed using a combination of molecular modeling techniques. We generated three-dimensional quantitative structure-activity relationship (3D-QSAR) models based on three alignments for both comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA) to highlight the structural requirements for thrombin protein inhibition. In addition to the 3D-QSAR study, Topomer CoMFA model also was established with a higher leave-one-out cross-validation q2 and a non-cross-validation r2, which suggest that the three models have good predictive ability. The results indicated that the steric, hydrophobic and electrostatic fields play key roles in QSAR model. Furthermore, we employed molecular docking and re-docking simulation explored the binding relationship of the ligand and the receptor protein in detail. Molecular docking simulations identified several key interactions that were also indicated through 3D-QSAR analysis. On the basis of the obtained results, two compounds were designed and predicted by three models, the biological evaluation in vitro (IC50) demonstrated that these molecular models were effective for the development of novel potent thrombin inhibitors.
- Dong, Ming-Hui,Chen, Hai-Feng,Ren, Yu-Jie,Shao, Fang-Ming
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- Design, synthesis, biological evaluation and molecular docking studies of dabigatran analogs as potential thrombin inhibitors
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A series of fluorinated dabigatran analogs were designed and synthesized. All the target compounds were characterized by 1H NMR, 13C NMR, and FT-ICR-MS. The thrombin inhibitory activities of the new synthesized compounds were also evaluated in vitro. The results show that compound 12a has the highest IC50 of thrombin inhibition (IC50 = 5.41 nM). Moreover, molecular docking simulation was carried out to elucidate the conformations of the compounds and key amino acid residues at the active site of thrombin protein. The results show there is an appropriate relationship between IC50 and the docking scores for compounds 12a-e. We suggest that the hydrogen bond interaction between Asp189, Gly219 of thrombin and the compounds appear to play major role in thrombin inhibition.
- Chen, Hai-Feng,Dong, Ming-Hui,Ren, Yu-Jie,Wang, Fei
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p. 347 - 357
(2016/01/09)
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- Synthesis and biological evaluation of novel dabigatran derivatives as thrombin inhibitors
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A novel series of 3-[{2-[(4-carbamimidoylphenylamino)methyl]-1-substituted-1H-benzoimidazole-5-carbonyl}(3-chloro-4-fluorophenyl)amino]propionic derivatives of dabigatran was synthesized. The structures of the compounds were characterized by 1H NMR, 13C NMR, HRMS, and elemental analysis. The compounds were screened for in vitro thrombin inhibitory activity. The results indicated that the compounds had low to moderate inhibitory activity. The compounds with N-methyl and N-ethyl side chains had much greater inhibitory activity against thrombin than those with other side chains.
- Li, Chun Lei,Ren, Yu Jie
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p. 735 - 752
(2016/04/26)
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- Multi-substituted 4-methyl ester derivative of amino benzonitrile trunk and its preparation and use
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The invention provides new ester derivatives with a general formula (I) shown in the specification of multi-substituted 4-methylamino-benzamidine or pharmaceutically acceptable salts, wherein A1, A2, A3 and A4 in the formula are as defined in the specification. The compounds have an anticoagulant effect and can be used for preparing medicaments for preventing and treating thromboembolic diseases.
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Paragraph 0096; 0108-0110
(2018/01/19)
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- A PROCESS FOR PREPARATION OF DABIGATRAN ETEXILATE MESYLATE AND INTERMEDIATES THEREOF
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The present invention relates to an improved process for the preparation of Dabigatran etexilate and its acid addition salts thereof, wherein the said process substantially eliminates the potential impurities. The present invention also relates to an intermediate of Dabigatran etexilate and process for preparation thereof.
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Page/Page column 41; 42
(2015/09/28)
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- IMPROVED PROCESS FOR PREPARATION OF DABIGATRAN ETEXILATE AND ITS NOVEL INTERMEDIATE
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Provided are intermediates for preparing dabigatran etexilate i.e. isopropanol solvate of l-methyl-2-[N-(4-amidinophenyl)-aminomethyl] benzimidazol-5-yl-carboxylicacid-N-(2-pyridyl)-N-(2-ethoxy carbonyl ethyl)-amide hydrochloride of formula (Vila) and crystalline form II of l-methyl-2-[N-(4-amidinophenyl)-aminomethyl] benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxy carbonyl ethyl)-amide hydrochloride of formula (VII).
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Paragraph 60; 61
(2013/03/26)
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- INTERMEDIATES AND PROCESS FOR PREPARING A THROMBIN SPECIFIC INHIBITOR
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Process for the preparation of a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R1 and R2 represent H; or either R1 represents ethyl and R2 represents n-hexyloxycarbonyl that applies to industrial scale, novel intermediates useful for the preparation thereof, and processes of preparing said intermediates.
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Page/Page column 18-19
(2012/02/01)
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- A METHOD FOR THE PREPARATION OF DABIGATRAN
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A method for the manufacture of dabigatran of formula VIII, in which the product of a reaction of 4-ethylamino-3-nitrobenzoic acid chloride with ethyl-3-(pyridin-2- ylamino)propanoate, is converted to the hydrochloride using a hydrogen chloride solution producing the compound of formula III-HC1, in which the nitro group is reduced by means of a reaction with sodium dithionite, and the resulting compound of formula IV is subjected to a reaction with [(4-cyanophenyl)amino] acetic acid and oxalic acid, the product of this reaction Vl-oxal is then subjected to hydrolysis and a reaction with ammonium carbonate to produce the intermediate of formula VII-HCl, which is then converted to dabigatran by means of a reaction with hexyl chloroformate.
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Page/Page column 8-9
(2009/10/22)
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- Novel non-benzimidazole chk2 kinase inhibitors
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In a recent paper, [Arienti, K. L.; Brunmark, A.; Axe, F. U.; McClure, K. M.; Lee, A.; Blevitt, J.; Neff, D. K.; Huang, L.; Crawford, S.; Chennagiri, R. P.; Karlsson, L.; Brietenbucher, J. G. J. Med. Chem. 2005, 48, 1873], we described the discovery of a class of benzimidazole chk2 kinase inhibitors, exemplified by compound 1, which had radio-protective effects in human T-cells subjected to ionizing radiation. Here, a series of non-benzimidazole analogs intended to define the scope of the SAR about this new series of inhibitor, and allow for refinement of the binding model of these compounds to the chk2 kinase is described.
- McClure, Kelly J.,Huang, Liming,Arienti, Kristen L.,Axe, Frank U.,Brunmark, Anders,Blevitt, Jon,Guy Breitenbucher
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p. 1924 - 1928
(2007/10/03)
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- Structure-based design of novel potent nonpeptide thrombin inhibitors
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The clinical syndromes of thromboembolism are evoked by an excessive stimulation of the coagulation cascade. In this context, the serine protease thrombin plays a key role. Considerable efforts have therefore been devoted to the discovery of safe, orally active inhibitors of this enzyme. On the basis of the X-ray crystal structure of the peptidelike thrombin inhibitor NAPAP complexed with bovine thrombin, we have designed a new structural class of nonpeptidic inhibitors employing a 1,2,5-trisubstituted benzimidazole as the central scaffold. Supported by a series of X-ray structure analyses, we optimized the activity of these compounds. Thrombin inhibition in the lower nanomolar range could be achieved although the binding energy mainly results from nonpolar, hydrophobic interactions. To improve in vivo potency, we increased the overall hydrophilicity of the molecules by introducing carboxylate groups. The very polar compound 24 (BIBR 953) exhibited the most favorable activity profile in vivo. This zwitterionic molecule was converted into the double-prodrug 31 (BIBR 1048), which showed strong oral activity in different animal species. On the basis of these results, 31 was chosen for clinical development.
- Hauel, Norbert H.,Nar, Herbert,Priepke, Henning,Ries, Uwe,Stassen, Jean-Marie,Wienen, Wolfgang
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p. 1757 - 1766
(2007/10/03)
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- Design and synthesis of a novel water soluble benzotetrazepinone
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In order to confer water solubility to the benzotetrazepinone ring system, the synthesis of 12 was undertaken. The design and synthesis of 12 were based upon previously established structural requirements for the stability of the 1,2,3,5-tetrazepin-4-one ring system. Tetrazepinone 12 was extremely water soluble and was 10-fold more potent than its imidazo-1,2,3,5-tetrazin-4-one counterpart 1a, against the human MCF-7 breast cancer cell line. (C) 2000 Elsevier Science Ltd.
- Dumont-Hornebeck, Beatrice,Strube, Yi Ning,Vasilescu, Daniela,Jean-Claude, Bertrand Jacques
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p. 2325 - 2327
(2007/10/03)
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