Hepatitis C virus NS3-4A serine protease inhibitors: Use of a P2–P1 cyclopropyl alanine combination for improved potency

Bogen, Stéphane; Saksena, Anil K.; Arasappan, Ashok; Gu, Haifeng; Njoroge, F. George; Girijavallabhan, Viyyoor; Pichardo, John; Butkiewicz, Nancy; Prongay, Andrew; Madison, Vincent

doi:10.1016/j.bmcl.2005.07.009

Cited by 25 publications

(14 citation statements)

References 28 publications

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“…This inhibitor lacks a P1' group and has a simple primary amide terminus [57]. The compound was dosed in patients infected with HCV as a tripeptide equilibrium mixture of 2 P1 diastereomers and was derived from a longer scaffold that traversed P2' to P3, such as compound 19, which demonstrated moderate binding affinity for the HCV NS3•4A protease [58,59].…”

Section: Sch 503034mentioning

confidence: 99%

Discovery and Development of VX-950, a Novel, Covalent, and Reversible Inhibitor of Hepatitis C Virus NS3.4A Serine Protease

Lin

Kwong²,

Perni³

2006

IDDT

209

107

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The hepatitis C virus (HCV) NS3.4A protease, which is essential for viral replication, is considered one of the most attractive targets for developing novel anti-HCV therapies. However, discovery of potent and selective small-molecule inhibitors of HCV NS3.4A protease as oral drug candidates has been hampered by the shallow substrate-binding groove of the protease. Serine trap warheads have been used to covalently anchor inhibitor scaffolds and to increase their affinity to the protease. This review will examine the evolution of covalent inhibitors of the HCV NS3.4A protease from early aldehyde molecules to alpha-ketoamide inhibitors. Kinetic and structural studies of alpha-ketoacid and alpha-ketoamide inhibitors revealed an unusual mechanism of binding in the catalytic site. Optimization of alpha-ketoamide scaffolds by scientists at Vertex and Eli Lilly led to the discovery of VX-950, a novel, potent, selective inhibitor of HCV NS3.4A protease. VX-950 possesses excellent antiviral activity in both HCV replicon cells and human fetal hepatocytes infected with HCV-positive patient sera. In addition, VX-950 exhibits a favorable pharmacokinetic profile in several animal species and demonstrates potent inhibition of the HCV NS3.4A protease activity in a mouse model. In a recent phase 1b clinical trial, VX-950 was able to rapidly reduce the plasma viral load of patients chronically infected with genotype 1 HCV by a mean approximately 3 log(10) in 2 days. The median viral load reduction was 4.4 log(10) for the best dose group after 14 days of dosing. The pre-clinical profile and early clinical data of VX-950 will be discussed in this review.

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Section: Sch 503034mentioning

confidence: 99%

Discovery and Development of VX-950, a Novel, Covalent, and Reversible Inhibitor of Hepatitis C Virus NS3.4A Serine Protease

Lin

Kwong²,

Perni³

2006

IDDT

209

107

View full text Add to dashboard Cite

show abstract

“…1). 8 However, we reasoned that less peptidic inhibitors would be more desirable not only for cellular activity but also to get benefits such as oral bioavailability and improved pharmacokinetics. From the hydrogen bond model depicted in Figure 2, it is clear that substrate and inhibitor were bonded through a combination of hydrogen bonds and side-chain hydrophobic interactions.…”

mentioning

confidence: 99%

“…8 While 1 showed very good enzyme inhibitory activity ðK Ã i ¼ 0:015 lMÞ, it obviously lacked drug-like properties. Alteration of peptides to peptidomimetics could afford compounds with improved biological potencies and increased resistance to enzymatic degradation.…”

mentioning

confidence: 99%

Depeptidization efforts on α-ketoamide inhibitors of HCV NS3-4A serine protease: Effect on HCV replicon activity

Bogen¹,

Ruan²,

Liu³

et al. 2006

Bioorganic & Medicinal Chemistry Letters

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“…The drug targets selected for this project were crystal structures of DEN2V [63,64,68], WNV [68,129] and HCV ( [130][131][132][133][134] proteases. The project screened a small molecule library that contained 2.2 million drug-like and lead-like molecules extracted from the ZINC database [83].…”

Section: Ddd-t Phase 1: Virtual Screening Methodologymentioning

confidence: 99%

New Approaches to Structure-Based Discovery of Dengue Protease Inhibitors

Tomlinson¹,

Malmstrom²,

Watowich³

2009

IDDT

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Dengue virus (DENV), a member of the family Flaviviridae, presents a tremendous threat to global health since an estimated 2.5 billion people worldwide are at risk for epidemic transmission. DENV infections are primarily restricted to sub-tropical and tropical regions; however, there is concern that the virus will spread into new regions including the United States. There are no approved antiviral drugs or vaccines to combat dengue infection, although DENV vaccines have entered Phase 3 clinical trials. Drug discovery and development efforts against DENV and other viral pathogens must overcome specificity, efficacy, safety, and resistance challenges before the shortage of licensed drugs to treat viral infections can be relieved. Current drug discovery methods are largely inefficient and thus relatively ineffective at tackling the growing threat to public health presented by emerging and remerging viral pathogens. This review discusses current and newly implemented structure-based computational efforts to discover antivirals that target the DENV NS3 protease, although it is clear that these computational tools can be applied to most disease targets.

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Hepatitis C virus NS3-4A serine protease inhibitors: Use of a P2–P1 cyclopropyl alanine combination for improved potency

Cited by 25 publications

References 28 publications

Discovery and Development of VX-950, a Novel, Covalent, and Reversible Inhibitor of Hepatitis C Virus NS3.4A Serine Protease

Discovery and Development of VX-950, a Novel, Covalent, and Reversible Inhibitor of Hepatitis C Virus NS3.4A Serine Protease

Depeptidization efforts on α-ketoamide inhibitors of HCV NS3-4A serine protease: Effect on HCV replicon activity

New Approaches to Structure-Based Discovery of Dengue Protease Inhibitors

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