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浮米每周文献快讯：HCV专题前沿 作者：浮米网 来源：浮米网 2014-03-24 1评论
1. Discovery and Development of Hepatitis C Virus NS5A Replication Complex Inhibitors.期刊：J. Med. Chem., 2014, 57 (5), pp 1643–1672 DOI: 10.1021/jm401793m 公司/组织：Bristol-Myers Squibb 候选药物化学结构式/活性：
靶点/作用机制：丙型肝炎病毒NS5A 摘要原文：Lead inhibitors that target the function of the hepatitis C virus ( HCV) nonstructural 5A (NS5A) protein have been identified by phenotypic screening campaigns using HCV subgenomic replicons. The demonstration of antiviral activity in HCV-infected subjects by the HCV NS5A replication complex inhibitor (RCI) daclatasvir (1) spawned considerable interest in this mechanistic approach. In this Perspective, we summarize the medicinal chemistry studies that led to the discovery of 1 and other chemotypes for which resistance maps to the NS5A protein and provide synopses of the profiles of many of the compounds currently in clinical trials. We also summarize what is currently known about the NS5A protein and the studies using NS5A RCIs and labeled analogues that are helping to illuminate aspects of both protein function and inhibitor interaction. We conclude with a synopsis of the results of notable clinical trials with HCV NS5A RCIs. 备注：丙型肝炎病毒NS5A (nonstructural 5A) 蛋白在病毒复制周期中发挥重要的作用。NS5A抑制剂已作为一类治疗丙型肝炎的潜在有效药物。 2. Discovery and Development of Simeprevir (TMC435), a HCV NS3/4A Protease Inhibitor.期刊：J. Med. Chem., 2014, 57 (5), pp 1673–1693 DOI: 10.1021/jm401507s 公司/组织： Janssen 候选药物化学结构式/活性：
靶点/作用机制：丙型肝炎病毒NS3蛋白酶 摘要原文：Hepatitis C virus is a blood-borne infection and the leading cause of chronic liver disease (including cirrhosis and cancer) and liver transplantation. Since the identification of HCV in 1989, there has been an extensive effort to identify and improve treatment options. An important milestone was reached in 2011 with the approval of the first-generation HCV NS3/4A protease inhibitors. However, new therapies are needed to improve cure rates, shorten treatment duration, and improve tolerability. Here we summarize the extensive medicinal chemistry effort to develop novel P2 cyclopentane macrocyclic inhibitors guided by HCV NS3 protease assays, the cellular replicon system, structure-based design, and a panel of DMPK assays. The selection of compound 29 (simeprevir, TMC435) as clinical candidate was based on its excellent biological, PK, and safety pharmacology profile. Compound 29 has recently been approved for treatment of chronic HCV infection in combination with pegylated interferon-α and ribavirin in Japan, Canada, and USA. 备注：治疗丙型肝炎的药物靶点包括NS3/4A蛋白酶、RNA依赖性RNA多聚酶NS5B以及NS5A RNA结合蛋白。 Boceprevir和Telaprevir作为第一代HCV NS3/4A蛋白酶抑制剂并用于与peg-IFN-α和Ribavirin联合治疗基因型1的HCV感染。 3. Discovery and Early Clinical Evaluation of BMS-605339, a Potent and Orally Efficacious Tripeptidic Acylsulfonamide NS3 Protease Inhibitor for the Treatment of Hepatitis C Virus Infection.期刊：J. Med. Chem., 2014, 57 (5), pp 1708–1729 DOI: 10.1021/jm401840s 公司/组织：Bristol-Myers Squibb 候选药物化学结构式/活性：
靶点/作用机制：HCV NS3/4A 蛋白酶 摘要原文：The discovery of BMS-605339 (35), a tripeptidic inhibitor of the NS3/4A enzyme, is described. This compound incorporates a cyclopropylacylsulfonamide moiety that was designed to improve the potency of carboxylic acid prototypes through the introduction of favorable nonbonding interactions within the S1′ site of the protease. The identification of 35 was enabled through the optimization and balance of critical properties including potency and pharmacokinetics (PK). This was achieved through modulation of the P2* subsite of the inhibitor which identified the isoquinoline ring system as a key template for improving PK properties with further optimization achieved through functionalization. A methoxy moiety at the C6 position of this isoquinoline ring system proved to be optimal with respect to potency and PK, thus providing the clinical compound 35 which demonstrated antiviral activity in HCV-infected patients. 备注：HCV存在六大类基因型（GT1-6）。基于医疗需求，GT1是目前研究针对的重点。治疗HCV GT1主要利用PEG-IFN-α和Ribavirin联合目前已获批的NS3蛋白酶抑制剂Boceprevir和Telaprevir。这两个蛋白酶抑制剂剂量服用为一日三次，且这样的配方可能会诱导产生耐药性。 4. The Discovery of Asunaprevir (BMS-650032), An Orally Efficacious NS3 Protease Inhibitor for the Treatment of Hepatitis C Virus Infection.期刊：J. Med. Chem., 2014, 57 (5), pp 1730–1752 DOI: 10.1021/jm500297k 公司/组织：Bristol-Myers Squibb 候选药物化学结构式/活性：
作用靶点/机制：HCV NS3/4A蛋白酶抑制剂 摘要原文：The discovery of asunaprevir (BMS-650032, 24) is described. This tripeptidic acylsulfonamide inhibitor of the NS3/4A enzyme is currently in phase III clinical trials for the treatment of hepatitis C virus infection. The discovery of 24 was enabled by employing an isolated rabbit heart model to screen for the cardiovascular (CV) liabilities (changes to HR and SNRT) that were responsible for the discontinuation of an earlier lead from this chemical series, BMS-605339 (1), from clinical trials. The structure–activity relationships (SARs) developed with respect to CV effects established that small structural changes to the P2* subsite of the molecule had a significant impact on the CV profile of a given compound. The antiviral activity, preclincial PK profile, and toxicology studies in rat and dog supported clinical development of BMS-650032 (24). 备注：Asunaprevir (BMS -650032)已进入临床III期试验。 5.Discovery of Danoprevir (ITMN-191/R7227), a Highly Selective and Potent Inhibitor of Hepatitis C Virus (HCV) NS3/4A Protease.期刊：J. Med. Chem., 2014, 57 (5), pp 1753–1769 DOI: 10.1021/jm400164c 公司/组织：Array BioPharma & InterMune Inc. 候选药物化学结构式/活性： 作用靶点/机制：HCV NS3/4A蛋白酶抑制剂 摘要原文：HCV serine protease NS3 represents an attractive drug target because it is not only essential for viral replication but also implicated in the viral evasion of the host immune response pathway through direct cleavage of key proteins in the human innate immune system. Through structure-based drug design and optimization, macrocyclic peptidomimetic molecules bearing both a lipophilic P2 isoindoline carbamate and a P1/P1′ acylsulfonamide/acylsulfamide carboxylic acid bioisostere were prepared that possessed subnanomolar potency against the NS3 protease in a subgenomic replicon-based cellular assay (Huh-7). Danoprevir (compound 49) was selected as the clinical development candidate for its favorable potency profile across multiple HCV genotypes and key mutant strains and for its good in vitro ADME profiles and in vivo target tissue (liver) exposures across multiple animal species. X-ray crystallographic studies elucidated several key features in the binding of danoprevir to HCV NS3 protease and proved invaluable to our iterative structure-based design strategy. 6. Discovery of Hepatitis C Virus NS3-4A Protease Inhibitors with Improved Barrier to Resistance and Favorable Liver Distribution期刊：J. Med. Chem., 2014, 57 (5), pp 1770–1776 DOI: 10.1021/jm400121t 公司/组织：Boehringer Ingelheim 候选药物化学结构式/活性：
靶点/作用机制：HCV NS3/4A蛋白酶抑制剂 摘要原文：Given the emergence of resistance observed for the current clinical-stage hepatitis C virus (HCV) NS3 protease inhibitors, there is a need for new inhibitors with a higher barrier to resistance. We recently reported our rational approach to the discovery of macrocyclic acylsulfonamides as HCV protease inhibitors addressing potency against clinically relevant resistant variants. Using X-ray crystallography of HCV protease variant/inhibitor complexes, we shed light on the complex structural mechanisms by which the D168V and R155K residue mutations confer resistance to NS3 protease inhibitors. Here, we disclose SAR investigation and ADME/PK optimization leading to the identification of inhibitors with significantly improved potency against the key resistant variants and with increased liver partitioning. 7. Ligand Bioactive Conformation Plays a Critical Role in the Design of Drugs That Target the Hepatitis C Virus NS3 Protease期刊：J. Med. Chem., 2014, 57 (5), pp 1777–1789 DOI: 10.1021/jm401338c 公司/组织：Boehringer Ingelheim 候选药物化学结构式/活性：
靶点/作用机制：HCV NS3/4A蛋白酶抑制剂 摘要原文：A ligand-focused strategy employed NMR, X-ray, modeling, and medicinal chemistry to expose the critical role that bioactive conformation played in the design of a variety of drugs that target the HCV protease. The bioactive conformation (bound states) were determined for key inhibitors identified along our drug discovery pathway from the hit to clinical compounds. All adopt similar bioactive conformations for the common core derived from the hit peptide DDIVPC. A carefully designed SAR analysis, based on the advanced inhibitor 1 in which the P1 to P3 side chains and the N-terminal Boc were sequentially truncated, revealed a correlation between affinity and the relative predominance of the bioactive conformation in the free state. Interestingly, synergistic conformation effects on potency were also noted. Comparisons with clinical and recently marketed drugs from the pharmaceutical industry showed that all have the same core and similar bioactive conformations. This suggested that the variety of appendages discovered for these compounds also properly satisfy the bioactive conformation requirements and allowed for a large variety of HCV protease drug candidates to be designed. 8. Discovery of the First C-Nucleoside HCV Polymerase Inhibitor (GS-6620) with Demonstrated Antiviral Response in HCV Infected Patients.期刊：J. Med. Chem., 2014, 57 (5), pp 1812–1825 DOI: 10.1021/jm400201a 公司/组织：Gilead Sciences 候选药物化学结构式/活性：
靶点/作用机制：HCV NS5B多聚酶抑制剂 摘要原文：Hepatitis C virus (HCV) infection presents an unmet medical need requiring more effective treatment options. Nucleoside inhibitors (NI) of HCV polymerase (NS5B) have demonstrated pan-genotypic activity and durable antiviral response in the clinic, and they are likely to become a key component of future treatment regimens. NI candidates that have entered clinical development thus far have all been N-nucleoside derivatives. Herein, we report the discovery of a C-nucleoside class of NS5B inhibitors. Exploration of adenosine analogs in this class identified 1′-cyano-2′-C-methyl 4-aza-7,9-dideaza adenosine as a potent and selective inhibitor of NS5B. A monophosphate prodrug approach afforded a series of compounds showing submicromolar activity in HCV replicon assays. Further pharmacokinetic optimization for sufficient oral absorption and liver triphosphate loading led to identification of a clinical development candidate GS-6620. In a phase I clinical study, the potential for potent activity was demonstrated but with high intra- and interpatient pharmacokinetic and pharmacodynamic variability. 备注： 9. Use of 2′-Spirocyclic Ethers in HCV Nucleoside Design.期刊：J. Med. Chem., 2014, 57 (5), pp 1826–1835 DOI: 10.1021/jm401224y 公司/组织：Pharmasset, Inc. 候选药物化学结构式/活性： 靶点/作用机制：HCV NS5B多聚酶抑制剂 摘要原文：Conformationally restricted 2′-spironucleosides and their prodrugs were synthesized as potential anti-HCV agents. Although the replicon activity of the new agents containing pyrimidine bases was modest, the triphosphate of a 2′-oxetane cytidine analogue demonstrated potent intrinsic biochemical activity against the NS5B polymerase, with IC50 = 8.48 μM. Activity against NS5B bearing the S282T mutation was reduced. Phosphoramidate prodrugs of a 2′-oxetane 2-amino-6-O-methyl-purine nucleoside demonstrated potent anti-HCV activity in vitro, and the corresponding triphosphate retained similar potent activity against both wild-type and S282T HCV NS5B polymerase. 10.Nucleotide Prodrugs of 2′-Deoxy-2′-spirooxetane Ribonucleosides as Novel Inhibitors of the HCV NS5B Polymerase期刊：J. Med. Chem., 2014, 57 (5), pp 1836–1844 DOI: 10.1021/jm4015422 公司/组织：Janssen 候选药物化学结构式/活性： 靶点/作用机制：HCV NS5B多聚酶抑制剂 摘要原文：The limited efficacy, in particular against the genotype 1 virus, as well as the variety of side effects associated with the current therapy for hepatitis C virus (HCV) infection necessitates more efficacious drugs. We found that phosphoramidate prodrugs of 2′-deoxy-2′-spirooxetane ribonucleosides form a novel class of HCV NS5B RNA-dependent RNA polymerase inhibitors, displaying EC50 values ranging from 0.2 to >98 μM, measured in the Huh7-replicon cell line, with no apparent cytotoxicity (CC50 > 98.4 μM). Confirming recent findings, the 2′-spirooxetane moiety was identified as a novel structural motif in the field of anti-HCV nucleosides. A convenient synthesis was developed that enabled the synthesis of a broad set of nucleotide prodrugs with varying substitution patterns. Extensive formation of the triphosphate metabolite was observed in both rat and human hepatocyte cultures. In addition, after oral dosing of several phosphoramidate derivatives of compound 21 to rats, substantial hepatic levels of the active triphosphate metabolite were found. 11. Conformation-Based Restrictions and Scaffold Replacements in the Design of Hepatitis C Virus Polymerase Inhibitors: Discovery of Deleobuvir (BI 207127).期刊： J. Med. Chem., 2014, 57 (5), pp 1845–1854 DOI: 10.1021/jm4011862 公司/组织：Boehringer Ingelheim 候选药物化学结构式/活性： 靶点/作用机制：HCV NS5B多聚酶抑制剂 摘要原文：Conformational restrictions of flexible torsion angles were used to guide the identification of new chemotypes of HCV NS5B inhibitors. Sites for rigidification were based on an acquired conformational understanding of compound binding requirements and the roles of substituents in the free and bound states. Chemical bioisosteres of amide bonds were explored to improve cell-based potency. Examples are shown, including the design concept that led to the discovery of the phase III clinical candidate deleobuvir (BI 207127). The structure-based strategies employed have general utility in drug design. 12. Discovery and Preclinical Characterization of the Cyclopropylindolobenzazepine BMS-791325, A Potent Allosteric Inhibitor of the Hepatitis C Virus NS5B Polymerase.期刊：J. Med. Chem., 2014, 57 (5), pp 1855–1879 DOI: 10.1021/jm4016894 公司/组织：Bristol-Myers Squibb 候选药物化学结构式/活性： 靶点/作用机制：HCV NS5B多聚酶抑制剂 摘要原文：Described herein are structure–activity relationship studies that resulted in the optimization of the activity of members of a class of cyclopropyl-fused indolobenzazepine HCV NS5B polymerase inhibitors. Subsequent iterations of analogue design and syntheses successfully addressed off-target activities, most notably human pregnane X receptor (hPXR) transactivation, and led to significant improvements in the physicochemical properties of lead compounds. Those analogues exhibiting improved solubility and membrane permeability were shown to have notably enhanced pharmacokinetic profiles. Additionally, a series of alkyl bridged piperazine carboxamides was identified as being of particular interest, and from which the compound BMS-791325 (2) was found to have distinguishing antiviral, safety, and pharmacokinetic properties that resulted in its selection for clinical evaluation. 13. Discovery and Early Development of TMC647055, a Non-Nucleoside Inhibitor of the Hepatitis C Virus NS5B Polymerase.期刊：J. Med. Chem., 2014, 57 (5), pp 1880–1892 DOI: 10.1021/jm401396p 公司/组织：Janssen 候选药物化学结构式/活性：
靶点/作用机制：HCV NS5B多聚酶抑制剂 摘要原文：Structure-based macrocyclization of a 6-carboxylic acid indole chemotype has yielded potent and selective finger-loop inhibitors of the hepatitis C virus (HCV) NS5B polymerase. Lead optimization in conjunction with in vivo evaluation in rats identified several compounds showing (i) nanomolar potency in HCV replicon cells, (ii) limited toxicity and off-target activities, and (iii) encouraging preclinical pharmacokinetic profiles characterized by high liver distribution. This effort culminated in the identification of TMC647055 (10a), a nonzwitterionic 17-membered-ring macrocycle characterized by high affinity, long polymerase residence time, and broad genotypic coverage. In vitro results of the combination of 10a with the HCV protease inhibitor TMC435 (simeprevir) supported an evaluation of this combination in patients with regard to virus suppression and resistance emergence. In a phase 1b trial with HCV genotype 1-infected patients, 10a was considered to be safe and well-tolerated and demonstrated potent antiviral activity, which was further enhanced in a combination study with TMC435. 14. Discovery of GS-9669, a Thumb Site II Non-Nucleoside Inhibitor of NS5B for the Treatment of Genotype 1 Chronic Hepatitis C Infection.期刊：J. Med. Chem., 2014, 57 (5), pp 1893–1901 DOI: 10.1021/jm401420j 公司/组织：Gilead Sciences, Inc. 候选药物化学结构式/活性： 靶点/作用机制：HCV NS5B多聚酶抑制剂 摘要原文：Investigation of thiophene-2-carboxylic acid HCV NS5B site II inhibitors, guided by measurement of cell culture medium binding, revealed the structure–activity relationships for intrinsic cellular potency. The pharmacokinetic profile was enhanced through incorporation of heterocyclic ethers on the N-alkyl substituent. Hydroxyl groups were incorporated to modulate protein binding. Intrinsic potency was further improved through enantiospecific introduction of an olefin in the N-acyl motif, resulting in the discovery of the phase 2 clinical candidate GS-9669. The unexpected activity of this compound against the clinically relevant NS5B M423T mutant, relative to the wild type, was shown to arise from both the N-alkyl substituent and the N-acyl group. 15. Discovery of a Potent Boronic Acid Derived Inhibitor of the HCV RNA-Dependent RNA Polymerase.期刊：J. Med. Chem., 2014, 57 (5), pp 1902–1913 DOI: 10.1021/jm400317w 公司/组织：GlaxoSmithKline 候选药物化学结构式/活性： 靶点/作用机制：HCV NS5B多聚酶抑制剂 摘要原文：A boronic acid moiety was found to be a critical pharmacophore for enhanced in vitro potency against wild-type hepatitis C replicons and known clinical polymorphic and resistant HCV mutant replicons. The synthesis, optimization, and structure–activity relationships associated with inhibition of HCV replication in a subgenomic replication system for a series of non-nucleoside boron-containing HCV RNA-dependent RNA polymerase (NS5B) inhibitors are described. A summary of the discovery of 3 (GSK5852), a molecule which entered clinical trials in subjects infected with HCV in 2011, is included. 备注：候选药物3在单剂量420 mg时能统计显著地降低血清HCV RNA，但还未进入 临床试验。 16. Discovery of N-[4-[6-tert-Butyl-5-methoxy-8-(6-methoxy-2-oxo-1H-pyridin-3-yl)-3-quinolyl]phenyl]methanesulfonamide (RG7109), a Potent Inhibitor of the Hepatitis C Virus NS5B Polymerase.期刊：J. Med. Chem., 2014, 57 (5), pp 1914–1931 DOI: 10.1021/jm401329s 公司/组织：Roche Inc. 候选药物化学结构式/活性： 靶点/作用机制：HCV NS5B多聚酶抑制剂 摘要原文：In the past few years, there have been many advances in the efforts to cure patients with hepatitis C virus (HCV). The ultimate goal of these efforts is to develop a combination therapy consisting of only direct-antiviral agents (DAAs). In this paper, we discuss our efforts that led to the identification of a bicyclic template with potent activity against the NS5B polymerase, a critical enzyme on the life cycle of HCV. In continuation of our exploration to improve the stilbene series, the 3,5,6,8-tetrasubstituted quinoline core was identified as replacement of the stilbene moiety. 6-Methoxy-2(1H)-pyridone was identified among several heterocyclic headgroups to have the best potency. Solubility of the template was improved by replacing a planar aryl linker with a saturated pyrrolidine. Profiling of the most promising compounds led to the identification of quinoline 41 (RG7109), which was selected for advancement to clinical development.
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