共查询到20条相似文献,搜索用时 0 毫秒
1.
Barbara Pacini Salvatore Avolio Caterina Ercolani Uwe Koch Giovanni Migliaccio Frank Narjes Laura Pacini Licia Tomei Steven Harper 《Bioorganic & medicinal chemistry letters》2009,19(21):6245-6249
A series of 2-(3-thienyl)-5,6-dihydroxypyrimidine-4-carboxylic acid inhibitors of the hepatitis C virus (HCV) NS5B polymerase enzyme are reported. Sulfonyl urea substituted analogs in this series proved to be the most potent active site non-nucleoside inhibitors of NS5B reported to date. These compounds had low nanomolar enzyme inhibition across HCV genotypes 1–3 and showed single digit micromolar inhibition in the HCV replicon assay. This improved cell-based activity allowed the binding mode of these compounds to be probed by selection of resistant mutations against compound 21. The results generated are in broad agreement with the previously proposed binding model for this compound class. 相似文献
2.
Frank Ruebsam Chinh V. Tran Lian-Sheng Li Sun Hee Kim Alan X. Xiang Yuefen Zhou Julie K. Blazel Zhongxiang Sun Peter S. Dragovich Jingjing Zhao Helen M. McGuire Douglas E. Murphy Martin T. Tran Nebojsa Stankovic David A. Ellis Alberto Gobbi Richard E. Showalter Stephen E. Webber Amit M. Shah Mei Tsan Leo Kirkovsky 《Bioorganic & medicinal chemistry letters》2009,19(2):451-458
5,6-Dihydro-1H-pyridin-2-one analogs were discovered as a novel class of inhibitors of genotype 1 HCV NS5B polymerase. Among these, compound 4ad displayed potent inhibitory activities in biochemical and replicon assays (IC50 (1b) < 10 nM; IC50 (1a) < 25 nM, EC50 (1b) = 16 nM), good in vitro DMPK properties, as well as moderate oral bioavailability in monkeys (F = 24%). 相似文献
3.
Kumar DV Rai R Brameld KA Somoza JR Rajagopalan R Janc JW Xia YM Ton TL Shaghafi MB Hu H Lehoux I To N Young WB Green MJ 《Bioorganic & medicinal chemistry letters》2011,21(1):82-87
Hepatitis C virus (HCV) infection is treated with a combination of peginterferon alfa-2a/b and ribavirin. To address the limitations of this therapy, numerous small molecule agents are in development, which act by directly affecting key steps in the viral life-cycle. Herein we describe our discovery of quinolone derivatives, novel small-molecules that inhibit NS5b polymerase, a key enzyme of the viral life-cycle. A crystal structure of a quinoline analog bound to NS5B reveals that this class of compounds binds to allosteric site-II (non-nucleoside inhibitor-site 2, NNI-2) of this protein. 相似文献
4.
David McGowan Origène Nyanguile Maxwell D. Cummings Sandrine Vendeville Koen Vandyck Walter Van den Broeck Carlo W. Boutton Hendrik De Bondt Ludo Quirynen Katie Amssoms Jean-François Bonfanti Stefaan Last Klara Rombauts Abdellah Tahri Lili Hu Frédéric Delouvroy Katrien Vermeiren Geneviève Vandercruyssen Liesbet Van der Helm Erna Cleiren Pierre Raboisson 《Bioorganic & medicinal chemistry letters》2009,19(9):2492-2496
Optimization through parallel synthesis of a novel series of hepatitis C virus (HCV) NS5B polymerase inhibitors led to the identification of (R)-11-(4-benzyloxy-2-fluorophenyl)-6-hydroxy-3,3-dimethyl-10-(6-methylpyridine-2-carbonyl)-2,3,4,5,10,11-hexahydro-dibenzo[b,e][1,4]diazepin-1-one 11zc and (R)-11-(4-benzyloxy-2-fluorophenyl)-6-hydroxy-3,3-dimethyl-10-(2,5-dimethyloxazol-4-carbonyl)-2,3,4,5,10,11-hexahydro-dibenzo[b,e][1,4]diazepin-1-one 11zk as potent (replicon EC50 = 400 nM and 270 nM, respectively) and selective (CC50 > 20 μM) inhibitors of HCV replication. These data warrant further lead-optimization efforts. 相似文献
5.
I. Novel HCV NS5B polymerase inhibitors: discovery of indole 2-carboxylic acids with C3-heterocycles
Anilkumar GN Lesburg CA Selyutin O Rosenblum SB Zeng Q Jiang Y Chan TY Pu H Vaccaro H Wang L Bennett F Chen KX Duca J Gavalas S Huang Y Pinto P Sannigrahi M Velazquez F Venkatraman S Vibulbhan B Agrawal S Butkiewicz N Feld B Ferrari E He Z Jiang CK Palermo RE McMonagle P Huang HC Shih NY Njoroge G Kozlowski JA 《Bioorganic & medicinal chemistry letters》2011,21(18):5336-5341
SAR development of indole-based palm site inhibitors of HCV NS5B polymerase exemplified by initial indole lead 1 (NS5B IC(50)=0.9 μM, replicon EC(50)>100 μM) is described. Structure-based drug design led to the incorporation of novel heterocyclic moieties at the indole C3-position which formed a bidentate interaction with the protein backbone. SAR development resulted in leads 7q (NS5B IC(50)=0.032 μM, replicon EC(50)=1.4 μM) and 7r (NS5B IC(50)=0.017 μM, replicon EC(50)=0.3 μM) with improved enzyme and replicon activity. 相似文献
6.
Yan S Appleby T Gunic E Shim JH Tasu T Kim H Rong F Chen H Hamatake R Wu JZ Hong Z Yao N 《Bioorganic & medicinal chemistry letters》2007,17(1):28-33
Isothiazole analogs were discovered as a novel class of active-site inhibitors of HCV NS5B polymerase. The best compound has an IC(50) of 200 nM and EC(50) of 100 nM, which is a significant improvement over the starting inhibitor (1). The X-ray complex structure of 1 with HCV NS5B was obtained at a resolution of 2.2A, revealing that the inhibitor is covalently linked with Cys 366 of the 'primer-grip'. Furthermore, it makes considerable contacts with the C-terminus, beta-loop, and more importantly, to the active-site of the enzyme. The uniqueness of this binding mode offers a new insight for the rational design of novel inhibitors for HCV NS5B polymerase. 相似文献
7.
Chan L Pereira O Reddy TJ Das SK Poisson C Courchesne M Proulx M Siddiqui A Yannopoulos CG Nguyen-Ba N Roy C Nasturica D Moinet C Bethell R Hamel M L'Heureux L David M Nicolas O Courtemanche-Asselin P Brunette S Bilimoria D Bédard J 《Bioorganic & medicinal chemistry letters》2004,14(3):797-800
Further SAR studies on the thiophene-2-carboxylic acids are reported. These studies led to the identification of a series of tertiary amides that show inhibition of both HCV NS5B polymerase in vitro and HCV subgenomic RNA replication in Huh-7 cells. Structural insights about the bioactive conformation of this class of molecules were deduced from a combination of modeling and transferred NOE (trNOE) studies. 相似文献
8.
Chan L Das SK Reddy TJ Poisson C Proulx M Pereira O Courchesne M Roy C Wang W Siddiqui A Yannopoulos CG Nguyen-Ba N Labrecque D Bethell R Hamel M Courtemanche-Asselin P L'Heureux L David M Nicolas O Brunette S Bilimoria D Bédard J 《Bioorganic & medicinal chemistry letters》2004,14(3):793-796
The discovery of a novel class of HCV NS5B polymerase inhibitors, 3-arylsulfonylamino-5-phenyl-thiophene-2-carboxylic acids is described. SAR studies have yielded several potent inhibitors of HCV polymerase as well as of HCV subgenomic RNA replication in Huh-7 cells. 相似文献
9.
Kumar DV Rai R Brameld KA Riggs J Somoza JR Rajagopalan R Janc JW Xia YM Ton TL Hu H Lehoux I Ho JD Young WB Hart B Green MJ 《Bioorganic & medicinal chemistry letters》2012,22(1):300-304
The discovery and optimization of a novel class of quinolone small-molecules that inhibit NS5B polymerase, a key enzyme of the HCV viral life-cycle, is described. Our research led to the replacement of a hydrolytically labile ester functionality with bio-isosteric heterocycles. An X-ray crystal structure of a key analog bound to NS5B facilitated the optimization of this series of compounds to afford increased activity against the target enzyme and in the cell-based replicon assay system. 相似文献
10.
Liu Y Lim BH Jiang WW Flentge CA Hutchinson DK Madigan DL Randolph JT Wagner R Maring CJ Kati WM Molla A 《Bioorganic & medicinal chemistry letters》2012,22(11):3747-3750
Aryl dihydrouracil derivatives were identified from high throughput screening as potent inhibitors of HCV NS5B polymerase. The aryl dihydrouracil derivatives were shown to be non-competitive with respect to template RNA and elongation nucleotide substrates. They demonstrated genotype 1 specific activity towards HCV NS5B polymerases. Structure activity relationships and genotype specific activities of aryl dihydrouracil derivatives suggested that they bind to the palm initiation nucleotide pocket, a hypothesis which was confirmed by studies with polymerases containing mutations in various inhibitor binding sites. Therefore, aryl dihydrouracil derivatives represent a novel class of palm initiation site inhibitors of HCV NS5B polymerase. 相似文献
11.
Kyle Parcella Andrew Nickel Brett R. Beno Steven Sheriff Changhong Wan Ying-Kai Wang Susan B. Roberts Nicholas A. Meanwell John F. Kadow 《Bioorganic & medicinal chemistry letters》2017,27(2):295-298
Alkoxyanthranilic acid derivatives have been identified to inhibit HCV NS5B polymerase, binding in an allosteric site located at the convergence of the palm and thumb regions. Information from co-crystal structures guided the structural design strategy. Ultimately, two independent structural modifications led to a similar shift in binding mode that when combined led to a synergistic improvement in potency and the identification of inhibitors with sub-micromolar HCV NS5B binding potency. 相似文献
12.
Ding Y Smith KL Varaprasad CV Chang E Alexander J Yao N 《Bioorganic & medicinal chemistry letters》2007,17(3):841-845
Several thiazolone-based sulfonamides were prepared, utilizing various hetero-aryl sulfonyl chlorides and different aldehydes, as inhibitors of NS5B polymerase, to target HCV. The best compound showed 0.6 microM [corrected] of IC50 inhibitory activity. 相似文献
13.
《Bioorganic & medicinal chemistry letters》2019,29(24):126104
Hepatitis C virus (HCV) NS5B polymerase is a prime target for the development of direct-acting antiviral drugs for the treatment of chronic HCV infection. Several novel and potent HCV NS5B non-nucleoside inhibitors with unique tetracyclic bezonfuran-based structures were prepared and evaluated. Similar to clinical developmental compound MK-8876, N-linked (compounds 1 and 2) and C-linked (compounds 3 and 4) tetracyclic structures maintained broad spectrum anti-replicon potency profiles and demonstrated moderate to excellent oral bioavailability and pharmacokinetic parameters across the three preclinical animal species. To better understand the importance of tetracyclic structures related to pan genotypic potency profiles especially against clinically relevant GT1a variants, the teracycles with different ring size were prepared and in vitro evaluations suggested compounds with six number ring have better overall potency profiles. 相似文献
14.
Identification and characterization of coumestans as novel HCV NS5B polymerase inhibitors 总被引:1,自引:0,他引:1
Kaushik-Basu N Bopda-Waffo A Talele TT Basu A Costa PR da Silva AJ Sarafianos SG Noël F 《Nucleic acids research》2008,36(5):1482-1496
The hepatitis C virus (HCV) NS5B is essential for viral RNA replication and is therefore a prime target for development of HCV replication inhibitors. Here, we report the identification of a new class of HCV NS5B inhibitors belonging to the coumestan family of phytoestrogens. Based on the in vitro NS5B RNA-dependent RNA polymerase (RdRp) inhibition in the low micromolar range by wedelolactone, a naturally occurring coumestan, we evaluated the anti-NS5B activity of four synthetic coumestan analogues bearing different patterns of substitutions in their A and D rings, and observed a good structure-activity correlation. Kinetic characterization of coumestans revealed a noncompetitive mode of inhibition with respect to nucleoside triphosphate (rNTP) substrate and a mixed mode of inhibition towards the nucleic acid template, with a major competitive component. The modified order of addition experiments with coumestans and nucleic acid substrates affected the potencies of the coumestan inhibitors. Coumestan interference at the step of NS5B-RNA binary complex formation was confirmed by cross-linking experiments. Molecular docking of coumestans within the allosteric site of NS5B yielded significant correlation between their calculated binding energies and IC(50) values. Coumestans thus add to the diversifying pool of anti-NS5B agents and provide a novel scaffold for structural refinement and development of potent NS5B inhibitors. 相似文献
15.
Anilkumar GN Selyutin O Rosenblum SB Zeng Q Jiang Y Chan TY Pu H Wang L Bennett F Chen KX Lesburg CA Duca J Gavalas S Huang Y Pinto P Sannigrahi M Velazquez F Venkatraman S Vibulbhan B Agrawal S Ferrari E Jiang CK Huang HC Shih NY George Njoroge F Kozlowski JA 《Bioorganic & medicinal chemistry letters》2012,22(1):713-717
Development of SAR at the C2 position of indole lead 1, a palm site inhibitor of HCV NS5B polymerase (NS5B IC(50)=0.053μM, replicon EC(50)=4.8μM), is described. Initial screening identified an acyl sulfonamide moiety as an isostere for the C2 carboxylic acid group. Further SAR investigation resulted in identification of acyl sufonamide analog 7q (NS5B IC(50)=0.039μM, replicon EC(50)=0.011μM) with >100-fold improved replicon activity. 相似文献
16.
Robert T. Hendricks Jay B. Fell James F. Blake John P. Fischer John E. Robinson Stacey R. Spencer Peter J. Stengel April L. Bernacki Vincent J.P. Leveque Sophie Le Pogam Sonal Rajyaguru Isabel Najera John A. Josey Jason R. Harris Steven Swallow 《Bioorganic & medicinal chemistry letters》2009,19(13):3637-3641
The importance of internal hydrogen bonding in a series of benzothiadiazine and 1,4-benzothiazine NS5b inhibitors has been explored. Computational analysis has been used to compare the protonated vs. anionic forms of each series and we demonstrate that activity against HCV NS5b polymerase is best explained using the anionic forms. The syntheses and structure–activity relationships for a variety of new analogs are also discussed. 相似文献
17.
Wang M Ng KK Cherney MM Chan L Yannopoulos CG Bedard J Morin N Nguyen-Ba N Alaoui-Ismaili MH Bethell RC James MN 《The Journal of biological chemistry》2003,278(11):9489-9495
X-ray crystal structures of two non-nucleoside analogue inhibitors bound to hepatitis C virus NS5B RNA-dependent RNA polymerase have been determined to 2.0 and 2.9 A resolution. These noncompetitive inhibitors bind to the same site on the protein, approximately 35 A from the active site. The common features of binding include a large hydrophobic region and two hydrogen bonds between both oxygen atoms of a carboxylate group on the inhibitor and two main chain amide nitrogen atoms of Ser(476) and Tyr(477) on NS5B. The inhibitor-binding site lies at the base of the thumb domain, near its interface with the C-terminal extension of NS5B. The location of this inhibitor-binding site suggests that the binding of these inhibitors interferes with a conformational change essential for the activity of the polymerase. 相似文献
18.
Pace P Nizi E Pacini B Pesci S Matassa V De Francesco R Altamura S Summa V 《Bioorganic & medicinal chemistry letters》2004,14(12):3257-3261
Screening of the in-house sample collection for compounds with HCV NS5B RNA dependent RNA polymerase inhibition led to the identification of a new lead. Afterwards, we discovered that the screening lead, rather than containing the expected structure 1, was comprised of roughly a 1:1 mixture of meconic acid 2 and its monoethyl ester 3, with all inhibitory potency residing with 3. We propose that this compound shares critical common features for activity with alpha,gamma-diketoacids inhibitors previously discovered by our group. SAR around this molecule will be presented to provide an improved basis for structure-based ligand design. 相似文献
19.
Timothy A. Stammers René Coulombe Jean Rancourt Bounkham Thavonekham Gulrez Fazal Sylvie Goulet Araz Jakalian Dominic Wernic Youla Tsantrizos Marc-André Poupart Michael Bös Ginette McKercher Louise Thauvette George Kukolj Pierre L. Beaulieu 《Bioorganic & medicinal chemistry letters》2013,23(9):2585-2589
A novel series of non-nucleoside thumb pocket 2 HCV NS5B polymerase inhibitors were derived from a fragment-based approach using information from X-ray crystallographic analysis of NS5B-inhibitor complexes and iterative rounds of parallel synthesis. Structure-based drug design strategies led to the discovery of potent sub-micromolar inhibitors 11a–c and 12a–c from a weak-binding fragment-like structure 1 as a starting point. 相似文献
20.
Canales E Carlson JS Appleby T Fenaux M Lee J Tian Y Tirunagari N Wong M Watkins WJ 《Bioorganic & medicinal chemistry letters》2012,22(13):4288-4292
The use of a tri-substituted acylhydrazine as an isostere of a tertiary amide was explored in a series of HCV NS5B thumb site II inhibitors. Direct replacement generated an analog with similar conformational and physicochemical properties. The series was extended to produce compounds with potent binding affinities and encouraging levels of cellular potency. 相似文献