1-Aminocyclopropaneboronic Acid:  Synthesis and Incorporation into an Inhibitor of Hepatitis C Virus NS3 Protease

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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“…A series of penta-and hexa-peptide compounds (5) showed good potency in enzyme assays (e.g. K i = 8 nM for R = CH 2 CH 3 ) [31,32].…”

Section: Boronatesmentioning

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

211

107

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“…Although 30 years of research has generated a wealth of information regarding the inhibition of various proteases by boronic acids, little has been reported regarding the general disposition of this class of compounds in humans (Kettner and Shenvi, 1984;Hussain et al, 1991;Kelly et al, 1993;Priestley and Decicco, 2000;London and Gabel, 2001;Yang et al, 2003). Moreover, the metabolic fate of boronic acids remains an unexplored area of biotransformation.…”

mentioning

confidence: 99%

Human Metabolism of the Proteasome Inhibitor Bortezomib: Identification of Circulating Metabolites

Pekol¹,

Daniels²,

Labutti³

et al. 2005

Drug Metabolism and Disposition

124

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ABSTRACT:Bortezomib [N-(2,3-pyrazine)carbonyl-L-phenylalanine-L-leucine boronic acid] is a potent first-in-class dipeptidyl boronic acid proteasome inhibitor that was approved in May 2003 in the United States for the treatment of patients with relapsed multiple myeloma where the disease is refractory to conventional lines of therapy. Bortezomib binds the proteasome via the boronic acid moiety, and therefore, the presence of this moiety is necessary to achieve proteasome inhibition. Metabolites in plasma obtained from patients receiving a single intravenous dose of bortezomib were identified and characterized by liquid chromatography/mass spectrometry (LC/MS) and liquid chromatography/tandem mass spectrometry (LC/MS/MS). Metabolite standards that were synthesized and characterized by LC/MS/MS and high field nuclear magnetic resonance spectroscopy (NMR) were used to confirm metabolite structures. The principal biotransformation pathway observed was oxidative deboronation, most notably to a pair of diastereomeric carbinolamide metabolites. Further metabolism of the leucine and phenylalanine moieties produced tertiary hydroxylated metabolites and a metabolite hydroxylated at the benzylic position, respectively. Conversion of the carbinolamides to the corresponding amide and carboxylic acid was also observed. Human liver microsomes adequately modeled the in vivo metabolism of bortezomib, as the principal circulating metabolites were observed in vitro. Using cDNA-expressed cytochrome P450 isoenzymes, it was determined that several isoforms contributed to the metabolism of bortezomib, including CYP3A4, CYP2C19, CYP1A2, CYP2D6, and CYP2C9. The development of bortezomib has provided an opportunity to describe the metabolism of a novel boronic acid pharmacophore.

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“…Side chains of Arg 61 and Lys166 are close to the S6 site, which explains the specificity of NS3/4A for aspartic or glutamic residues at the P6 position of the substrate. Consistent with the 3-D structure of the NS3-NS4A [21][22][23][24][25][26][27][28][29][30][31][32][33][34] complex, a synthetic peptide of the 12 residues in the middle portion of NS4A could be supplied as cofactor in various in vitro assays using the NS3 protease domain alone. Indeed, most of the HCV NS3/4A inhibitors discovered thus far, have been identified by using such biochemical assays.…”

Section: Ns3-4a Protease As An Anti-hcv Drug Targetmentioning

confidence: 68%

“…NS3 exerts optimal serine protease activity when complexed with the NS4A cofactor and a structural zinc molecule [4]. The structure of the protease domain alone or in complex with a peptide fragment of NS4A (NS4A [21][22][23][24][25][26][27][28][29][30][31][32][33][34] ), in the presence or absence of an inhibitor, has been revealed by X-ray crystallographic and NMR studies [4,5]. The NS3-NS4A 21-34 complex has chymotrypsin-like folding, including two β-barrel domains and four short α-helices.…”

Section: Ns3-4a Protease As An Anti-hcv Drug Targetmentioning

confidence: 99%

Discovery of Small-Molecule Inhibitors of HCV NS3-4A Protease as Potential Therapeutic Agents against HCV Infection

Chen¹,

Tan

2005

CMC

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Chronic infection with hepatitis C virus (HCV) is associated with liver cirrhosis that often leads to hepatic failure and hepatocellular carcinoma (HCC). HCV infection has become a global health threat and the main cause of adult liver transplants in developed nations. Current approved anti-HCV therapies (interferon and pegylated interferon alone or in combination with ribavirin) are not effective in eliminating the viral infection in a significant population of patients (e.g., those infected with HCV genotype 1). Furthermore, these therapies are plagued with many undesirable side effects. Therefore, the HCV epidemic represents a huge unmet medical need that has triggered intensive research efforts towards the development of more effective drugs. Given its essential role in the process of HCV replication, the viral NS3/4A serine protease is arguably the most thoroughly characterized HCV enzyme and the most intensively pursued anti-HCV target for drug development. This is further fueled by the successful use of small-molecule inhibitors of the human immunodeficiency virus (HIV) viral protease, which have had an impressive effect on HIV-related morbidity and mortality, offering hope that analogous drugs might also have a similar impact against HCV. Here, we review the recent progress and development of small-molecule inhibitors of the HCV NS3/4A protease. In particular, we focus on the discovery of VX-950, the latest HCV NS3-4A protease inhibitor to be advanced to clinical studies. While the challenges of designing potent inhibitors of the viral protease have been solved, as highlighted by BILN 2061 and VX-950, it is still too early to determine whether these efforts will eventually yield promising drug candidates. For the emerging small-molecule HCV inhibitors, viral resistance will likely be a big problem. Thus, combination therapy of different drugs with different targets/mechanisms will be necessary to effectively inhibit HCV replication. It is also hoped that a detail characterization of how the resistance mutations that affect NS3 inhibitor binding may provide useful information for the design of inhibitors with the potential to treat resistant viruses that may arise during chronic HCV infection.

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1-Aminocyclopropaneboronic Acid: Synthesis and Incorporation into an Inhibitor of Hepatitis C Virus NS3 Protease

Cited by 38 publications

References 20 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

Human Metabolism of the Proteasome Inhibitor Bortezomib: Identification of Circulating Metabolites

Discovery of Small-Molecule Inhibitors of HCV NS3-4A Protease as Potential Therapeutic Agents against HCV Infection

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