Design and synthesis of ethyl pyrrolidine-5,5-trans-lactams as inhibitors of hepatitis C virus NS3/4A protease

Slater, Martin J.; Andrews, David M.; Baker, Graham R.; Bethell, Susanne S.; Chaignot, Helene M.; Clarke, Berwyn; Coomber, Barry A.; Ellis, Malcolm; Good, Andrew C.; Gray, Norman M.; Hardy, G.; Jones, Paul S.; Mills, Gail; Robinson, Ed

doi:10.1016/s0960-894x(02)00789-8

Cited by 18 publications

(11 citation statements)

References 19 publications

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“…Subsequent P1 optimization led to a series of more potent inhibitors such as 5.2.0 and 5.2.1 with enzyme inhibitory IC 50 values of 4.4 µM and 0.51 µM , respectively [55]. Comparative evaluation of two pairs of the HCV NS3 protease inhibitors (5.1.1 vs. 5.1.0 and 5.2.1 vs. 5.2.0) clearly showed that amide linkage was preferred over sulfonamide at P1' position [54].…”

Section: General Sar Trendsmentioning

confidence: 99%

“…However, further development of this drug is reportedly suspended due to cardiac toxicity during long-term administration. Other series of structurally diverse NS3-protease substrate-based inhibitors in the nanomolar range have been disclosed, including α-ketoamides, boronic acids, phosphonates, hydrazinourea, α-ketoacids [7] and pyrrolidine-5,5-trans lactams [13]. Using structure-based computational and combinatorial-chemistry techniques, novel chemical scaffolds were generated, including the compound VX-950 (LY-570310), a tetrapeptidyl α -ketoamide based peptidomimetic inhibitor of HCV protease that has desirable potency and pharmacokinetic properties.…”

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

confidence: 99%

“…At this point, the N-protective group (TBS) was removed to unmask the lactam NH, which was then acylated to yield 5.1.6 or 5.1.7. These two intermediates were then converted to the final target inhibitors 5.1.0 and 5.1.1 upon N-deprotection (Cbz) and subsequent P3 Boc-valine attachment [54].…”

Section: Chemical Synthesismentioning

confidence: 99%

“…Only modest enzyme inhibitory activity was detected corresponding P1 isomers (bearing β-ethyl) were at least 3-fold less potent [54]. Subsequent P1 optimization led to a series of more potent inhibitors such as 5.2.0 and 5.2.1 with enzyme inhibitory IC 50 values of 4.4 µM and 0.51 µM , respectively [55].…”

Section: General Sar Trendsmentioning

confidence: 99%

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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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Section: General Sar Trendsmentioning

confidence: 99%

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

confidence: 99%

Section: Chemical Synthesismentioning

confidence: 99%

Section: General Sar Trendsmentioning

confidence: 99%

See 2 more Smart Citations

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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“…Here we describe the development of cell-based assay systems which extend and complement enzyme-based assays for the evaluation of potential antiviral compounds, specifically the pyrrolidine-5,5-trans-lactams (referred to below as translactams), which are inhibitors of NS3/4A protease (1,2,3,4,5,31,32). The gel-based assay, utilizing a recombinant vaccinia virus expressing NS3 to NS5 (rVV NS3-5), has the advantage of allowing direct visualization of the inhibition of NS3/4A processing.…”

mentioning

confidence: 99%

Development of Cell-Based Assays for In Vitro Characterization of Hepatitis C Virus NS3/4A Protease Inhibitors

Chung¹,

Carroll²,

Gray

et al. 2005

Antimicrob Agents Chemother

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A recombinant vaccinia virus, expressing the NS3-to-NS5 region of the N clone of hepatitis C virus (HCV), was generated and utilized both in a gel-based assay and in an enzyme-linked immunosorbent assay (ELISA) to evaluate the pyrrolidine-5,5-trans-lactams, a series of inhibitors of the HCV NS3/4A protease. The absolute levels of processed, mature HCV nonstructural proteins in this system were found to decrease in the presence of the trans-lactams. Monitoring of this reduction enabled end points and 50% inhibitory concentrations to be calculated in order to rank the active compounds according to potency. These compounds had no effect on the transcription or translation of the NS3-5 polyprotein at concentrations shown to inhibit NS3/4A protease, and they were shown to be specific inhibitors of this protease. The ELISA, originally developed using the vaccinia virus expression system, was modified to utilize Huh-7 cells containing an HCV replicon. Results with this assay correlated well with those obtained with the recombinant vaccinia virus assays. These results demonstrate the utility of these assays for the characterization of NS3/4A protease inhibitors. In addition, inhibitors of other viral targets, such as polymerase and helicase, can be evaluated in the context of the replicon ELISA.

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