Discovery of Vaniprevir (MK-7009), a Macrocyclic Hepatitis C Virus NS3/4a Protease Inhibitor

McCauley, John A.; McIntyre, Charles; Rudd, Michael T.; Nguyen, Kevin Tri; Romano, Joseph J.; Butcher, John W.; Gilbert, Kevin F.; Bush, Kimberly; Holloway, M. Katharine; Swestock, John; Wan, Bang-Lin; Carroll, Steven S.; DiMuzio, Jillian; Graham, Donald J.; Ludmerer, Steven W.; Mao, Shi‐Shan; Stahlhut, Mark W.; Fandozzi, Christine; Trainor, Nicole; Olsen, David B.; Vacca, Joseph P.; Liverton, Nigel J.

doi:10.1021/jm9015526

Cited by 175 publications

(108 citation statements)

References 44 publications

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“…Boceprevir (29) and telaprevir (37), both from this class, recently received regulatory approval as add-on therapy to pegylated interferon/ribavirin in the treatment of genotype 1-infected patients. A number of rapidly reversible NS3/4a protease inhibitors, including the P1-P3 constrained macrocyclic inhibitors TMC 435 (23) and danoprevir (45), the P2-P4 constrained macrocyclic inhibitor vaniprevir (33), the linear inhibitors BI 201335 (52), BMS650032 (47), and ABT-450 (51), and others of undisclosed structure, including GS 9451 and ACH-1625, are currently in mid-to late-stage development.…”

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confidence: 99%

“…The most advanced compound from this series, vaniprevir (24,33), is currently being evaluated in clinical trials in combination with pegylated interferon/ribavirin. Unlike the keto amide inhibitors, macrocycles do not derive potency from covalent linkage.…”

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confidence: 99%

“…A more detailed description of the synthetic procedures and structure activity data leading to MK-5172 are published (13). Vaniprevir (33), danoprevir (46), and TMC435 (41) were synthesized internally.…”

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MK-5172, a Selective Inhibitor of Hepatitis C Virus NS3/4a Protease with Broad Activity across Genotypes and Resistant Variants

Summa

Ludmerer

McCauley

et al. 2012

Antimicrob Agents Chemother

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HCV NS3/4a protease inhibitors are proven therapeutic agents against chronic hepatitis C virus infection, with boceprevir and telaprevir having recently received regulatory approval as add-on therapy to pegylated interferon/ribavirin for patients harboring genotype 1 infections. Overcoming antiviral resistance, broad genotype coverage, and a convenient dosing regimen are important attributes for future agents to be used in combinations without interferon. In this communication, we report the preclinical profile of MK-5172, a novel P2-P4 quinoxaline macrocyclic NS3/4a protease inhibitor currently in clinical development. The compound demonstrates subnanomolar activity against a broad enzyme panel encompassing major hepatitis C virus (HCV) genotypes as well as variants resistant to earlier protease inhibitors. In replicon selections, MK-5172 exerted high selective pressure, which yielded few resistant colonies. In both rat and dog, MK-5172 demonstrates good plasma and liver exposures, with 24-h liver levels suggestive of once-daily dosing. When administered to HCV-infected chimpanzees harboring chronic gt1a or gt1b infections, MK-5172 suppressed viral load between 4 to 5 logs at a dose of 1 mg/kg of body weight twice daily (b.i.d.) for 7 days. Based on its preclinical profile, MK-5172 is anticipated to be broadly active against multiple HCV genotypes and clinically important resistance variants and highly suited for incorporation into newer all-oral regimens.C hronic hepatitis C virus (HCV) infection afflicts more than 170 million people worldwide and is the major etiological cause of fibrosis, liver cirrhosis, and hepatocellular carcinoma (20,53). Current treatment relies on a backbone of interferon and ribavirin, a regimen with poor tolerability and toxicity (31, 34). Efforts to develop novel therapies to improve treatment have focused largely on direct acting antiviral agents (DAAs) (19), which therapeutically intervene with virally encoded components essential for HCV replication.Hepatitis C virus, a member of the Flaviviridae family of viruses in the Hepacivirus genus, is encoded by a 9.6-kb positivestrand RNA genome (8). It is initially translated into a single polypeptide that is subsequently cleaved into individual protein components by a combination of both host-and virally encoded proteases (2, 38). HCV protease inhibitors currently in clinical development span a variety of structural classes. The most advanced of these are keto amide compounds, which covalently bind to the active-site serine of the protease in a slowly reversible manner. Boceprevir (29) and telaprevir (37), both from this class, recently received regulatory approval as add-on therapy to pegylated interferon/ribavirin in the treatment of genotype 1-infected patients. A number of rapidly reversible NS3/4a protease inhibitors, including the P1-P3 constrained macrocyclic inhibitors TMC 435 (23) and danoprevir (45), the P2-P4 constrained macrocyclic inhibitor vaniprevir (33), the linear inhibitors BI 201335 (52), BMS650032 (47), and ABT-450 ...

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MK-5172, a Selective Inhibitor of Hepatitis C Virus NS3/4a Protease with Broad Activity across Genotypes and Resistant Variants

Summa

Ludmerer

McCauley

et al. 2012

Antimicrob Agents Chemother

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243

155

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“…These compounds were Vaniprevir (MK-7009, 7) [28,29], MK-1220 (8) [30], and MK-5172 (9) [31]. These compounds were developed following the development of MK-4519 (10) by Brown et al [32] which was optimized for genotype 1b potency.…”

Section: P2-p4 Macrocyclesmentioning

confidence: 99%

Untitled

2017

JAPLR

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Globally, Hepatitis C virus (HCV) is a leading cause of chronic liver disease, hepatocellular carcinoma and cirrhosis and the most common reason for liver transplantation. Presently, the most common treatment for HCV infected patients is the combinations of pegylated interferon and ribavirin that provide a sustained response in patients, but its side effects are brutal. Therefore, attempts have been made to target the two important enzymes, NS3 protease and NS5B RNA polymerase, that are crucial for the replication of HCV. The article presents the development of some NS3/4A protease inhibitors that have reached the final stages of clinical trials. Keywords: IntroductionHepatitis C virus (HCV) belongs to the family of Flaviviridae. This family also includes other viruses responsible for severe human diseases, such as yellow fever virus, dengue virus, St. Louis encephalitis virus, and West Nile virus. About 170 million people, estimating 3% of the global population are infected with HCV. Chronic HCV infection may lead to progressive liver injury, cirrhosis and in some cases hepatocellular carcinoma [1]. Hepatitis C virus is an envelope, positive single stranded RNA. Its genome is composed of 9.5kb and encodes a 3000 amino acid sequence residue polyprotein [2]. For HCV entry, human CD81 receptor is required which binds directly with E2 protein of HCV. This CD81 receptor is a widely distributed cell-surface tetraspanin that participates in the formation of molecular complexes on various cell types like hepatocytes, natural killer cells, B-lymphocytes, and T-lymphocytes. Thus, the HCV not only exploits hepatocytes but also modulates the host immune response.The HCV has principally two drug targets, its RNA polymerase and the protease enzymes. where the former catalyzes the RNA relication. This RNA-dependent RNA-polymerase (RdRp), however, lacks a proof reading activity which leads to a high mutation rate and a large number of mutations [3]. The HCV encodes a polyprotein of approximately 3000 amino acids [4], which is cleaved cotranslationally and post-translationally to produce four structural proteins (C, E1, E2, and p7) and six nonstructural (NS) proteins (NS2, NS3, NS4A, NS4B, NS5A and NS5B) [5][6][7]. Only the NS3-NS5B region of the polyprotein is required for genome replication in cell culture. NS3-NS4A, in which NS4A acts as a cofactor, is a serine protease belonging to trypsin/chemotrypsin superfamily. NS4A directs the localization of NS3 and modulates its enzyme activity [8]. NS3-NS4A is simply written as NS3/4A.It plays a critical role in producing the important components for viral replication by cleaving the scissile bond between NS3-NS4A. Based on the available structure of HCV protease, there are three possible sites for drug design, namely zinc binding site, NS4A binding groove, and substrate binding site, of which the last one has been found to be more promising. However, the design and development of NS3/4A inhibitors is more challenging than the design of inhibitors of other proteases such as...

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“…Vaniprevir (MK-7009) is a potent HCV NS3/4a protease inhibitor that is being evaluated for the treatment of HCV at the late stage of clinical studies ( Fig. 1) [4,5]. To ensure the supply of the drug for ongoing clinical studies, a chemical process amenable to production of multi-kilogram quantities of MK-7009 was required.…”

Section: Introductionmentioning

confidence: 99%

Application of Ring-Closing Metathesis Strategy to the Synthesis of Vaniprevir (MK-7009), a 20-Membered Macrocyclic HCV Protease Inhibitor

Chen

2012

Organometallics as Catalysts in the Fine Chemical Industry

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Vaniprevir (MK-7009) bearing a 20-membered macrocycle and chiral components is a highly efficacious HCV protease inhibitor aiming for the treatment of chronic infection of hepatitis C virus. The efficient macrocyclization coupled with the assembling of key chiral components is of great challenge for the large-scale production of this structurally complex molecule. In this chapter, a convergent synthesis with a longest sequence of nine steps featuring highly efficient macrocyclization via ring-closing metathesis (RCM) along with the improvement in the syntheses of key components will be described. RCM for the construction of 20-membered macrocycle using low catalyst loading (0.2 mol%) and practically high concentration (0.13 M) was achieved by simultaneous and slow addition of ruthenium catalyst and the diene substrate. The strategy of using RCM in this costeffective synthesis sets a new paradigm for the synthesis of several other macrocyclic HCV protease inhibitors at Merck Research Laboratories.

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Discovery of Vaniprevir (MK-7009), a Macrocyclic Hepatitis C Virus NS3/4a Protease Inhibitor

Cited by 175 publications

References 44 publications

MK-5172, a Selective Inhibitor of Hepatitis C Virus NS3/4a Protease with Broad Activity across Genotypes and Resistant Variants

MK-5172, a Selective Inhibitor of Hepatitis C Virus NS3/4a Protease with Broad Activity across Genotypes and Resistant Variants

Untitled

Application of Ring-Closing Metathesis Strategy to the Synthesis of Vaniprevir (MK-7009), a 20-Membered Macrocyclic HCV Protease Inhibitor

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