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浮米每周文献快讯：HCV专题（二） 前沿 作者：浮米网 来源：浮米网 2014-03-31 0评论 1. 原文标题及出处： Molecular Dynamics Simulations and Structure-Based Rational Design Lead to Allosteric HCV NS5B Polymerase Thumb Pocket 2 Inhibitor with Picomolar Cellular Replicon Potency. J. Med. Chem., 2014, 57 (5), pp 1932–1943 DOI: 10.1021/jm4004522 公司/组织：Boehringer Ingelheim 候选药物化学结构式/活性： 无标题 靶点/作用机制：HCV NS5B多聚酶抑制剂 摘要原文： The design and preliminary SAR of a new series of 1H-quinazolin-4-one (QAZ) allosteric HCV NS5B thumb pocket 2 (TP-2) inhibitors was recently reported. To support optimization efforts, a molecular dynamics (MD) based modeling workflow was implemented, providing information on QAZ binding interactions with NS5B. This approach predicted a small but critical ligand-binding induced movement of a protein backbone region which increases the pocket size and improves access to the backbone carbonyl groups of Val 494 and Pro 495. This localized backbone shift was consistent with key SAR results and was subsequently confirmed by X-ray crystallography. The MD protocol guided the design of inhibitors, exploiting novel H-bond interactions with the two backbone carbonyl groups, leading to the first thumb pocket 2 NS5B inhibitor with picomolar antiviral potency in genotype (gt) 1a and 1b replicons (EC50 = 120 and 110 pM, respectively) and with EC50 ≤ 80 nM against gt 2–6. 2. 原文标题及出处： Enantiomeric Atropisomers Inhibit HCV Polymerase and/or HIV Matrix: Characterizing Hindered Bond Rotations and Target Selectivity. J. Med. Chem., 2014, 57 (5), pp 1944–1951 DOI: 10.1021/jm401202a 公司/组织：Boehringer Ingelheim 候选药物化学结构式/活性： 20140331564502 靶点/作用机制：HCV NS5B多聚酶抑制剂 摘要原文： An anthranilic acid series of allosteric thumb pocket 2 HCV NS5B polymerase inhibitors exhibited hindered rotation along a covalent bond axis, and the existence of atropisomer chirality was confirmed by NMR, HPLC analysis on chiral supports, and computational studies. A thorough understanding of the concerted rotational properties and the influence exerted by substituents involved in this steric phenomenon was attained through biophysical studies on a series of truncated analogues. The racemization half-life of a compound within this series was determined to be 69 min, which was consistent with a class 2 atropisomer (intermediate conformational exchange). It was further found by X-ray crystallography that one enantiomer of a compound bound to the intended HCV NS5B polymerase target whereas the mirror image atropisomer was able to bind to an unrelated HIV matrix target. Analogues were then identified that selectively inhibited the former. These studies highlight that atropisomer chirality can lead to distinct entities with specific properties, and the phenomenon of atropisomerism in drug discovery should be evaluated and appropriately managed. 3. 原文标题及出处： Imidazopyridazine Hepatitis C Virus Polymerase Inhibitors. Structure–Activity Relationship Studies and the Discovery of a Novel, Traceless Prodrug Mechanism J. Med. Chem., 2014, 57 (5), pp 1964–1975 DOI: 10.1021/jm401337x 公司/组织：GlaxoSmithKline 候选药物化学结构式/活性： 20140331564503 靶点/作用机制：HCV NS5B多聚酶抑制剂 摘要原文： By reducing the basicity of the core heterocycle in a series of HCV NS5B inhibitors, the hERG liability was reduced. The SAR was then systematically explored in order to increase solubility and enable dose escalation while retaining potency. During this exploration, a facile decarboxylation was noted and was exploited as a novel prodrug mechanism. The synthesis and characterization of these prodrugs and their utilization in chronic toxicity studies are presented. 4. 原文标题及出处： HCV NS5A Replication Complex Inhibitors. Part 4.1 Optimization for Genotype 1a Replicon Inhibitory Activity. J. Med. Chem., 2014, 57 (5), pp 1976–1994 DOI: 10.1021/jm301796k 公司/组织：Bristol-Myers Squibb 候选药物化学结构式/活性： 20140331564504 靶点/作用机制：HCV NS5A 抑制剂 摘要原文： A series of symmetrical E-stilbene prolinamides that originated from the library-synthesized lead 3 was studied with respect to HCV genotype 1a (G-1a) and genotype 1b (G-1b) replicon inhibition and selectivity against BVDV and cytotoxicity. SAR emerging from an examination of the prolinamide cap region revealed 11 to be a selective HCV NS5A inhibitor exhibiting submicromolar potency against both G-1a and G-1b replicons. Additional structural refinements resulted in the identification of 30 as a potent, dual G-1a/1b HCV NS5A inhibitor. 5. 原文标题及出处： Hepatitis C Virus NS5A Replication Complex Inhibitors. Part 6: Discovery of a Novel and Highly Potent Biarylimidazole Chemotype with Inhibitory Activity Toward Genotypes 1a and 1b Replicons. J. Med. Chem., 2014, 57 (5), pp 1995–2012 DOI: 10.1021/jm4016203 公司/组织：Bristol-Myers Squibb 候选药物化学结构式/活性： 20140331564505 靶点/作用机制：HCV NS5A 抑制剂 摘要原文： A medicinal chemistry campaign that was conducted to address a potential genotoxic liability associated with an aniline-derived scaffold in a series of HCV NS5A inhibitors with dual GT-1a/-1b inhibitory activity is described. Anilides 3b and 3c were used as vehicles to explore structural modifications that retained antiviral potency while removing the potential for metabolism-based unmasking of the embedded aniline. This effort resulted in the discovery of a highly potent biarylimidazole chemotype that established a potency benchmark in replicon assays, particularly toward HCV GT-1a, a strain with significant clinical importance. Securing potent GT-1a activity in a chemotype class lacking overt structural liabilities was a critical milestone in the effort to realize the full clinical potential of targeting the HCV NS5A protein. 6. 原文标题及出处： Hepatitis C Virus NS5A Replication Complex Inhibitors: The Discovery of Daclatasvir J. Med. Chem., 2014, 57 (5), pp 2013–2032 DOI: 10.1021/jm401836p 公司/组织：Bristol-Myers Squibb 候选药物化学结构式/活性： 20140331564506 靶点/作用机制：HCV NS5A 抑制剂 摘要原文： The biphenyl derivatives 2 and 3 are prototypes of a novel class of NS5A replication complex inhibitors that demonstrate high inhibitory potency toward a panel of clinically relevant HCV strains encompassing genotypes 1–6. However, these compounds exhibit poor systemic exposure in rat pharmacokinetic studies after oral dosing. The structure–activity relationship investigations that improved the exposure properties of the parent bis-phenylimidazole chemotype, culminating in the identification of the highly potent NS5A replication complex inhibitor daclatasvir (33) are described. An element critical to success was the realization that the arylglycine cap of 2 could be replaced with an alkylglycine derivative and still maintain the high inhibitory potency of the series if accompanied with a stereoinversion, a finding that enabled a rapid optimization of exposure properties. Compound 33 had EC50 values of 50 and 9 pM toward genotype-1a and -1b replicons, respectively, and oral bioavailabilities of 38–108% in preclinical species. Compound 33 provided clinical proof-of-concept for the NS5A replication complex inhibitor class, and regulatory approval to market it with the NS3/4A protease inhibitor asunaprevir for the treatment of HCV genotype-1b infection has recently been sought in Japan. 7. 原文标题及出处： Discovery of Ledipasvir (GS-5885): A Potent, Once-Daily Oral NS5A Inhibitor for the Treatment of Hepatitis C Virus Infection. J. Med. Chem., 2014, 57 (5), pp 2033–2046 DOI: 10.1021/jm401499g 公司/组织：Gilead Sciences 候选药物化学结构式/活性： 20140331564507 靶点/作用机制：HCV NS5A 抑制剂 摘要原文： A new class of highly potent NS5A inhibitors with an unsymmetric benzimidazole-difluorofluorene-imidazole core and distal [2.2.1]azabicyclic ring system was discovered. Optimization of antiviral potency and pharmacokinetics led to the identification of 39 (ledipasvir, GS-5885). Compound 39 (GT1a replicon EC50 = 31 pM) has an extended plasma half-life of 37–45 h in healthy volunteers and produces a rapid >3 log viral load reduction in monotherapy at oral doses of 3 mg or greater with once-daily dosing in genotype 1a HCV-infected patients. 39 has been shown to be safe and efficacious, with SVR12 rates up to 100% when used in combination with direct-acting antivirals having complementary mechanisms. 8. 原文标题及出处： Novel Spiroketal Pyrrolidine GSK2336805 Potently Inhibits Key Hepatitis C Virus Genotype 1b Mutants: From Lead to Clinical Compound J. Med. Chem., 2014, 57 (5), pp 2058–2073 DOI: 10.1021/jm4013104 公司/组织：GlaxoSmithKline 候选药物化学结构式/活性： 20140331564508 靶点/作用机制：HCV NS5A 抑制剂 摘要原文： Rapid clinical progress of hepatitis C virus (HCV) replication inhibitors, including these selecting for resistance in the NS5A region (NS5A inhibitors), promises to revolutionize HCV treatment. Herein, we describe our explorations of diverse spiropyrrolidine motifs in novel NS5A inhibitors and a proposed interaction model. We discovered that the 1,4-dioxa-7-azaspiro[4.4]nonane motif in inhibitor 41H (GSK2236805) supported high potency against genotypes 1a and 1b as well as in genotype 1b L31V and Y93H mutants. Consistent with this, 41H potently suppressed HCV RNA in the 20-day RNA reduction assay. Pharmacokinetic and safety data supported further progression of 41H to the clinic. 9. 原文标题及出处： Integrated Strategies for Identifying Leads That Target the NS3 Helicase of the Hepatitis C Virus. J. Med. Chem., 2014, 57 (5), pp 2074–2090 DOI: 10.1021/jm401432c 公司/组织：Boehringer Ingelheim 候选药物化学结构式/活性： 20140331564509 靶点/作用机制：HCV NS3 解旋酶抑制剂 摘要原文： Future treatments for individuals infected by the hepatitis C virus (HCV) will likely involve combinations of compounds that inhibit multiple viral targets. The helicase of HCV is an attractive target with no known drug candidates in clinical trials. Herein we describe an integrated strategy for identifying fragment inhibitors using structural and biophysical techniques. Based on an X-ray structure of apo HCV helicase and in silico and bioinformatic analyses of HCV variants, we identified that one site in particular (labeled 3 + 4) was the most conserved and attractive pocket to target for a drug discovery campaign. Compounds from multiple sources were screened to identify inhibitors or binders to this site, and enzymatic and biophysical assays (NMR and SPR) were used to triage the most promising ligands for 3D structure determination by X-ray crystallography. Medicinal chemistry and biophysical evaluations focused on exploring the most promising lead series. The strategies employed here can have general utility in drug discovery. 10. 原文标题及出处： Discovery of Selective Small Molecule Type III Phosphatidylinositol 4-Kinase Alpha (PI4KIIIα) Inhibitors as Anti Hepatitis C (HCV) Agents. J. Med. Chem., 2014, 57 (5), pp 2091–2106 DOI: 10.1021/jm400781h 公司/组织：GlaxoSmithKline 候选药物化学结构式/活性： 20140331564510 靶点/作用机制：PI4KIIIα抑制剂 摘要原文： Hepatitis C virus (HCV) assembles many host cellular proteins into unique membranous replication structures as a prerequisite for viral replication, and PI4KIIIα is an essential component of these replication organelles. RNA interference of PI4KIIIα results in a breakdown of this replication complex and cessation of HCV replication in Huh-7 cells. PI4KIIIα is a lipid kinase that interacts with the HCV nonstructural 5A protein (NS5A) and enriches the HCV replication complex with its product, phosphoinositol 4-phosphate (PI4P). Elevated levels of PI4P at the endoplasmic reticulum have been linked to HCV infection in the liver of HCV infected patients.1 We investigated if small molecule inhibitors of PI4KIIIα could inhibit HCV replication in vitro. The synthesis and structure–activity relationships associated with the biological inhibition of PI4KIIIα and HCV replication are described. These efforts led directly to identification of quinazolinone 28 that displays high selectivity for PI4KIIIα and potently inhibits HCV replication in vitro. 备注：治疗HCV的传统方法是直接针对病毒的基因组。辅助策略为针对HCV复制过程中用到的宿主细胞成分。PI4KIIIα是HCV复制的必须的宿主因子。 11. 原文标题及出处： Hepatitis C Replication Inhibitors That Target the Viral NS4B Protein. J. Med. Chem., 2014, 57 (5), pp 2107–2120 DOI: 10.1021/jm400125h 公司/组织：GlaxoSmithKline 候选药物化学结构式/活性： 20140331564511 靶点/作用机制：HCV NS4B抑制剂 摘要原文： We describe the preclinical development and in vivo efficacy of a novel chemical series that inhibits hepatitis C virus replication via direct interaction with the viral nonstructural protein 4B (NS4B). Significant potency improvements were realized through isosteric modifications to our initial lead 1a. The temptation to improve antiviral activity while compromising physicochemical properties was tempered by the judicial use of ligand efficiency indices during lead optimization. In this manner, compound 1a was transformed into (+)-28a which possessed an improved antiviral profile with no increase in molecular weight and only a modest elevation in lipophilicity. Additionally, we employed a chimeric “humanized” mouse model of HCV infection to demonstrate for the first time that a small molecule with high in vitro affinity for NS4B can inhibit viral replication in vivo. This successful proof-of-concept study suggests that drugs targeting NS4B may represent a viable treatment option for curing HCV infection. 12. 原文标题及出处： Structure–Activity Relationship (SAR) Optimization of 6-(Indol-2-yl)pyridine-3-sulfonamides: Identification of Potent, Selective, and Orally Bioavailable Small Molecules Targeting Hepatitis C (HCV) NS4B. J. Med. Chem., 2014, 57 (5), pp 2121–2135 DOI: 10.1021/jm401621g 公司/组织：Merck 候选药物化学结构式/活性： 20140331564512 靶点/作用机制：HCV NS4B 抑制剂 摘要原文： A novel, potent, and orally bioavailable inhibitor of hepatitis C RNA replication targeting NS4B, compound 4t (PTC725), has been identified through chemical optimization of the 6-(indol-2-yl)pyridine-3-sulfonamide 2 to improve DMPK and safety properties. The focus of the SAR investigations has been to identify the optimal combination of substituents at the indole N-1, C-5, and C-6 positions and the sulfonamide group to limit the potential for in vivo oxidative metabolism and to achieve an acceptable pharmacokinetic profile. Compound 4t has excellent potency against the HCV 1b replicon, with an EC50 = 2 nM and a selectivity index of >5000 with respect to cellular GAPDH. Compound 4t has an overall favorable pharmacokinetic profile with oral bioavailability values of 62%, 78%, and 18% in rats, dogs, and monkeys, respectively, as well as favorable tissue distribution properties with a liver to plasma exposure ratio of 25 in rats. 13. 原文标题及出处： Highly Potent HCV NS4B Inhibitors with Activity against Multiple Genotypes. J. Med. Chem., 2014, 57 (5), pp 2161–2166 DOI: 10.1021/jm401646w 公司/组织：Gilead Sciences 候选药物化学结构式/活性： 20140331564513 靶点/作用机制：HCV NS4B 抑制剂 摘要原文： The exploration of novel inhibitors of the HCV NS4B protein that are based on a 2-oxadiazoloquinoline scaffold is described. Optimization to incorporate activity across genotypes led to a potent new series with broad activity, of which inhibitor 1 displayed the following EC50 values: 1a, 0.08 nM; 1b, 0.10 nM; 2a, 3 nM; 2b, 0.6 nM, 3a, 3.7 nM; 4a, 0.9 nM; 6a, 3.1 nM. |
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