共查询到20条相似文献,搜索用时 31 毫秒
1.
Kim SH Tran MT Ruebsam F Xiang AX Ayida B McGuire H Ellis D Blazel J Tran CV Murphy DE Webber SE Zhou Y Shah AM Tsan M Showalter RE Patel R Gobbi A LeBrun LA Bartkowski DM Nolan TG Norris DA Sergeeva MV Kirkovsky L Zhao Q Han Q Kissinger CR 《Bioorganic & medicinal chemistry letters》2008,18(14):4181-4185
A novel series of HCV NS5B polymerase inhibitors comprising 1,1-dioxoisothiazoles and benzo[b]thiophene-1,1-dioxides were designed, synthesized, and evaluated. SAR studies guided by structure-based design led to the identification of a number of potent NS5B inhibitors with nanomolar IC50 values. The most potent compound exhibited IC50 less than 10 nM against the genotype 1b HCV polymerase and EC50 of 70 nM against a genotype 1b replicon in cell culture. The DMPK properties of selected compounds were also evaluated. 相似文献
2.
Marcin Skoreński Aleksandra Milewska Krzysztof Pyrć Marcin Sieńczyk 《Journal of enzyme inhibition and medicinal chemistry》2019,34(1):8-14
West Nile virus (WNV) is a member of the flavivirus genus belonging to the Flaviviridae family. The viral serine protease NS2B/NS3 has been considered an attractive target for the development of anti-WNV agents. Although several NS2B/NS3 protease inhibitors have been described so far, most of them are reversible inhibitors. Herein, we present a series of α-aminoalkylphosphonate diphenyl esters and their peptidyl derivatives as potent inhibitors of the NS2B/NS3 protease. The most potent inhibitor identified was Cbz-Lys-Arg-(4-GuPhe)P(OPh)2 displaying Ki and k2/Ki values of 0.4 µM and 28 265 M?1s?1, respectively, with no significant inhibition of trypsin, cathepsin G, and HAT protease. 相似文献
3.
《Bioorganic & medicinal chemistry letters》2020,30(5):126932
A novel unsymmetrical structural class of HCV NS5A inhibitors showing picomolar range antiviral activity has been identified. An unsymmetrical lead compound 2, generated from a substructure of a known symmetrical inhibitor 1, was optimized by extension of its substituents to interact with the hitherto unexplored site of the target protein. This approach afforded novel highly potent unsymmetrical inhibitor 20, which not only equally inhibited HCV genotypes1a, 1b, and 2a with EC50 values in the picomolar range, but also inhibited the 1a Q30K mutant induced by a launched symmetrical inhibitor daclatasvir with an EC50 in the low nanomolar range. 相似文献
4.
《Bioorganic & medicinal chemistry》2020,28(1):115208
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Gentles RG Sheriff S Beno BR Wan C Kish K Ding M Zheng X Chupak L Poss MA Witmer MR Morin P Wang YK Rigat K Lemm J Voss S Liu M Pelosi L Roberts SB Gao M Kadow JF 《Bioorganic & medicinal chemistry letters》2011,21(8):2212-2215
Structure based rationales for the activities of potent N-benzyl-4-heteroaryl-1-(phenylsulfonyl)piperazine-2-carboxamide inhibitors of the hepatitis C viral polymerase are described herein. These compounds bind to the hepatitis C virus non-structural protein 5B (NS5B), and co-crystal structures of select examples from this series with NS5B are reported. Comparison of co-crystal structures of a potent analog with both NS5B genotype 1a and genotype 1b provides a possible explanation for the genotype-selectivity observed with this compound class and suggests opportunities for the further optimization of the series. 相似文献
7.
Iwona E. Weidlich Igor V. Filippov Jodian Brown Neerja Kaushik-Basu Ramalingam Krishnan Marc C. Nicklaus Ian F. Thorpe 《Bioorganic & medicinal chemistry》2013,21(11):3127-3137
Hepatitis C virus (HCV) is a global health challenge, affecting approximately 200 million people worldwide. In this study we developed SAR models with advanced machine learning classifiers Random Forest and k Nearest Neighbor Simulated Annealing for 679 small molecules with measured inhibition activity for NS5B genotype 1b. The activity was expressed as a binary value (active/inactive), where actives were considered molecules with IC50 ?0.95 μM. We applied our SAR models to various drug-like databases and identified novel chemical scaffolds for NS5B inhibitors. Subsequent in vitro antiviral assays suggested a new activity for an existing prodrug, Candesartan cilexetil, which is currently used to treat hypertension and heart failure but has not been previously tested for anti-HCV activity. We also identified NS5B inhibitors with two novel non-nucleoside chemical motifs. 相似文献
8.
Qingbei Zeng Anilkumar G. Nair Stuart B. Rosenblum Hsueh-Cheng Huang Charles A. Lesburg Yueheng Jiang Oleg Selyutin Tin-Yau Chan Frank Bennett Kevin X. Chen Srikanth Venkatraman Mousumi Sannigrahi Francisco Velazquez Jose S. Duca Stephen Gavalas Yuhua Huang Haiyan Pu Li Wang Joseph A. Kozlowski 《Bioorganic & medicinal chemistry letters》2013,23(24):6585-6587
The discovery of lead compound 2e was described. Its covalent binding to HCV NS5B polymerase enzyme was investigated by X-ray analysis. The results of distribution, metabolism and pharmacokinetics were reported. Compound 2e was demonstrated to be potent (replicon GT-1b EC50 = 0.003 μM), highly selective, and safe in in vitro and in vivo assays. 相似文献
9.
David A. DeGoey David A. Betebenner David J. Grampovnik Dachun Liu John K. Pratt Michael D. Tufano Wenping He Preethi Krishnan Tami J. Pilot-Matias Kennan C. Marsh Akhteruzzaman Molla Dale J. Kempf Clarence J. Maring 《Bioorganic & medicinal chemistry letters》2013,23(12):3627-3630
Efforts to improve the genotype 1a potency and pharmacokinetics of earlier naphthyridine-based HCV NS5A inhibitors resulted in the discovery of a novel series of pyrido[2,3-d]pyrimidine compounds, which displayed potent inhibition of HCV genotypes 1a and 1b in the replicon assay. SAR in this system revealed that the introduction of amides bearing an additional ‘E’ ring provided compounds with improved potency and pharmacokinetics. Introduction of a chiral center on the amide portion resulted in the observation of a stereochemical dependence for replicon potency and provided a site for the attachment of functional groups useful for improving the solubility of the series. Compound 21 was selected for administration in an HCV-infected chimpanzee. Observation of a robust viral load decline provided positive proof of concept for inhibition of HCV replication in vivo for the compound series. 相似文献
10.
Zheng X Hudyma TW Martin SW Bergstrom C Ding M He F Romine J Poss MA Kadow JF Chang CH Wan J Witmer MR Morin P Camac DM Sheriff S Beno BR Rigat KL Wang YK Fridell R Lemm J Qiu D Liu M Voss S Pelosi L Roberts SB Gao M Knipe J Gentles RG 《Bioorganic & medicinal chemistry letters》2011,21(10):2925-2929
Herein, we present initial SAR studies on a series of bridged 2-arylindole-based NS5B inhibitors. The introduction of bridging elements between the indole N1 and the ortho-position of the 2-aryl moiety resulted in conformationally constrained heterocycles that possess multiple additional vectors for further exploration. The binding mode and pharmacokinetic (PK) properties of select examples, including: 13-cyclohexyl-6-oxo-6,7-dihydro-5H-indolo[2,1-d][1,4]benzodiazepine-10-carboxylic acid (7) (IC50 = 0.07 μM, %F = 18), are reported. 相似文献
11.
A series of m-alkyl α,α,α-trifluoroacetophenones (1–5) was synthesized and evaluated as inhibitors of acetylcholinesterase from Torpedo california. All ketones (1–5) were found to be potent inhibitors of the enzyme; m-t-butyl α,α,α-trifluoroacetophenone (4) was the most potent inhibitor with a Ki value of 3.7 pM. 相似文献
12.
Martin SW Glunz P Beno BR Bergstrom C Romine JL Priestley ES Newman M Gao M Roberts S Rigat K Fridell R Qiu D Knobloh G Wang YK 《Bioorganic & medicinal chemistry letters》2011,21(10):2869-2872
Herein we report the identification and evaluation of a novel series of (E)-3-(1-cyclohexyl-1H-pyrazol-3-yl)-2-methylacrylic acid derivatives identified from a deannulation study performed on the reported benzimidazole NS5B inhibitor, 1. This resulted in the identification of (E)-3-(2-(4-((4′-cyano-4-(4-hydroxypiperidine-1-carbonyl)biphenyl-2-yl)methoxy)phenyl)-1-cyclohexyl-1H-imidazol-4-yl)-2-methylacrylic acid (11) as a potent inhibitor of NS5B. Potential pathways for the further optimization of this series are suggested. 相似文献
13.
《Bioorganic & medicinal chemistry》2020,28(20):115716
A series of novel small-molecule pan-genotypic hepatitis C virus (HCV) NS5A inhibitors with picomolar activity containing 2-[(2S)-pyrrolidin-2-yl]-5-[4-(4-{2-[(2S)-pyrrolidin-2-yl]-1H-imidazol-5-yl}buta-1,3-diyn-1-yl)phenyl]-1H-imidazole core was designed based on molecular modeling study and SAR analysis. The constructed in silico model and docking study provide a deep insight into the binding mode of this type of NS5A inhibitors. Based on the predicted binding interface we have prioritized the most crucial diversity points responsible for improving antiviral activity. The synthesized molecules were tested in a cell-based assay, and compound 1.12 showed an EC50 value in the range of 2.9–34 pM against six genotypes of NS5A HCV, including gT3a, and demonstrated favorable pharmacokinetic profile in rats. This lead compound can be considered as an attractive candidate for further clinical evaluation. 相似文献
14.
《Bioorganic & medicinal chemistry》2014,22(22):6344-6352
Dengue virus is endemic throughout tropical and subtropical regions, and cause severe epidemic diseases. The NS2B/NS3 protease is a promising drug target for dengue virus. Herein, we report the discovery and modification of a novel class of thiadiazoloacrylamide derivatives with potent inhibitory activity against the NS2B/NS3 protease. Thiadiazolopyrimidinone 1 was firstly determined as a new chemical structure against NS2B/NS3 from a commercial compound library. Then, we sought to identify similar compounds with the thiadiazoloacrylamide core that would exhibit better activity. A series of analogues were synthesized and fourteen of them were identified with strong inhibitory activities, in which the nitrile group in the linker part was discovered as an essential group for the inhibitory activity. The best of these (8b) demonstrated an IC50 at 2.24 μM based on in vitro DENV2 NS2B-NS3pro assays. 相似文献
15.
《Bioorganic & medicinal chemistry letters》2014,24(21):4984-4988
Previous investigations identified 2′-C-Me-branched ribo-C-nucleoside adenosine analogues, 1, which contains a pyrrolo[2,1-f][1,2,4]triazin-4-amine heterocyclic base, and 2, which contains an imidazo[2,1-f][1,2,4]triazin-4-amine heterocyclic base as two compounds with promising anti-HCV in vitro activity. This Letter describes the synthesis and evaluation of a series of novel analogues of these compounds substituted at the 2-, 7-, and 8-positions of the heterocyclic bases. A number of active new HCV inhibitors were identified but most compounds also demonstrated unacceptable cytotoxicity. However, the 7-fluoro analogue of 1 displayed good potency with a promising cytotherapeutic margin. 相似文献
16.
Gentles RG Ding M Zheng X Chupak L Poss MA Beno BR Pelosi L Liu M Lemm J Wang YK Roberts S Gao M Kadow J 《Bioorganic & medicinal chemistry letters》2011,21(10):3142-3147
Described herein is the initial optimization of (+/−) N-benzyl-4-heteroaryl-1-(phenylsulfonyl)piperazine-2-carboxamide (1), a hit discovered in a high throughput screen run against the NS5B polymerase enzyme of the hepatitis C virus. This effort resulted in the identification of (S)-N-sec-butyl-6-((R)-3-(4-(trifluoromethoxy)benzylcarbamoyl)-4-(4-(trifluoromethoxy)phenylsulfonyl)piperazin-1-yl)pyridazine-3-carboxamide (2), that displayed potent replicon activities against HCV genotypes 1b and 1a (EC50 1b/1a = 7/89 nM). 相似文献
17.
Moyi Liu Qiaoling Xu Su Guo Ruixi Zuo Yue Hong Yong Luo Yingxiu Li Ping Gong Yajing Liu 《Bioorganic & medicinal chemistry》2018,26(9):2621-2631
The hepatitis C virus (HCV) NS5B polymerase is an attractive target for the development of novel and selective inhibitors of HCV replication. In this paper, the design, synthesis, and preliminary SAR studies of novel inhibitors of HCV NS5B polymerase based on the structure of tegobuvir have been described. The efforts to optimize the antiviral potency and reduce the treatment side effects with respect to genotype 1b resulted in the discovery of compound 3, which exhibited an EC50 of 1.163?nM and a CC50 >200?nM in a cell-based HCV replicon system assay. Additionally, testing for inhibition of the hERG channel showed a marked improvement over tegobuvir and the pharmacokinetic properties of compound 3 indicated that it was worthy of further investigation as a non-nucleoside inhibitor of HCV NS5B polymerase. 相似文献
18.
Pierre L. Beaulieu René Coulombe Jianmin Duan Gulrez Fazal Cédrickx Godbout Oliver Hucke Araz Jakalian Marc-André Joly Olivier Lepage Montse Llinàs-Brunet Julie Naud Martin Poirier Nathalie Rioux Bounkham Thavonekham George Kukolj Timothy A. Stammers 《Bioorganic & medicinal chemistry letters》2013,23(14):4132-4140
We describe the structure-based design of a novel lead chemotype that binds to thumb pocket 2 of HCV NS5B polymerase and inhibits cell-based gt1 subgenomic reporter replicons at sub-micromolar concentrations (EC50 <200 nM). This new class of potent thumb pocket 2 inhibitors features a 1H-quinazolin-4-one scaffold derived from hybridization of a previously reported, low affinity thiazolone chemotype with our recently described anthranilic acid series. Guided by X-ray structural information, a key NS5B–ligand interaction involving the carboxylate group of anthranilic acid based inhibitors was replaced by a neutral two-point hydrogen bonding interaction between the quinazolinone scaffold and the protein backbone. The in vitro ADME and in vivo rat PK profile of representative analogs are also presented and provide areas for future optimization of this new class of HCV polymerase inhibitors. 相似文献
19.
Kim ND Chun H Park SJ Yang JW Kim JW Ahn SK 《Bioorganic & medicinal chemistry letters》2011,21(11):3329-3334
We report the use of pharmacophore-based virtual screening as an efficient tool for the discovery of novel HCV polymerase inhibitors. A three-dimensional pharmacophore model for the HCV-796 binding site, NNI site IV inhibitor, to the enzyme was built by means of the structure-based focusing module in Cerius2 program. Using these models as a query for virtual screening, we produced a successful example of using pharmacophore-based virtual screening to identify novel compounds with HCV replicon assay through inhibition of HCV polymerization. Among the hit compounds, compounds 1 and 2 showed 56% and 48% inhibition of NS5B polymerization activity at 20 μM, respectively. In addition, compound 1 also exhibited replicon activity with EC50 value of 2.16 μM. Following up the initial hit, we obtained derivatives of compound 1 and evaluated polymerization inhibition activity and HCV replicon assay. These results provide information necessary for the development of more potent NS5B inhibitors. 相似文献
20.
Pamela Donner John T. Randolph Peggy Huang Rolf Wagner Clarence Maring Ben Hock Lim Lynn Colletti Yaya Liu Rubina Mondal Jill Beyer Gennadiy Koev Kennan Marsh David Beno Kenton Longenecker Tami Pilot-Matias Warren Kati Akhter Molla Dale Kempf 《Bioorganic & medicinal chemistry letters》2013,23(15):4367-4369
Described herein is the development of a potent non-nucleoside, small molecule inhibitor of genotype 1 HCV NS5B Polymerase. A 23 μM inhibitor that was active against HCV polymerase was further elaborated into a potent single-digit nanomolar inhibitor of HCV NS5B polymerase by additional manipulation of the R and R1 substituents. Subsequent modifications to improve physical properties were made in an attempt to achieve an acceptable pharmacokinetic profile. 相似文献