Synthesis of BILN 2061, an HCV NS3 Protease Inhibitor with Proven Antiviral Effect in Humans

Faucher, Anne‐Marie; Bailey, Murray; Beaulieu, Pierre L.; Brochu, Christian; Duceppe, Jean‐Simon; Ferland, Jean-Marie; Ghiro, Élise; Gorys, Vida; Halmos, Ted; Kawai, Stephen H.; Poirier, Martin; Simoneau, Bruno; Tsantrizos, Youla S.; Llinàs‐Brunet, Montse

doi:10.1021/ol0489907

Cited by 111 publications

(74 citation statements)

References 30 publications

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“…In fact, an inhibition strategy involving the protease complex and facilitated by a co-factor enzyme has been successfully applied in the discovery of antiviral drugs against human immunodeficiency virus (HIV) and hepatitis C virus (HCV) [53] , and several inhibitors targeting the HCV NS3/4A protease have already entered into clinical trials [54][55][56] . Recently, varied types of potential inhibitors against the DENV2 NS2B/NS3 protease have been discovered [11, 23-25, 31, 57-59] and have provided important structural information for anti-DENV drug development.…”

Section: Discussionmentioning

confidence: 99%

Policresulen, a novel NS2B/NS3 protease inhibitor, effectively inhibits the replication of DENV2 virus in BHK-21 cells

Mao

et al. 2015

Acta Pharmacol Sin

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Aim: Dengue is a severe epidemic disease caused by dengue virus (DENV) infection, for which no effective treatment is available. The protease complex, consisting of nonstructural protein 3 (NS3) and its cofactor NS2B, plays a pivotal role in the replication of DENV, thus may be a potential target for anti-DENV drugs. Here, we report a novel inhibitor of DENV2 NS2B/NS3 protease and its antiviral action. Methods: An enzymatic inhibition assay was used for screening DENV2 NS2B/NS3 inhibitors. Cytotoxicity to BHK-21 cells was assessed with MTT assay. Antiviral activity was evaluated in BHK-21 cells transfected with Rlu-DENV-Rep. The molecular mechanisms of the antiviral action was analyzed using surface plasmon resonance, ultraviolet-visible spectral analysis and differential scanning calorimetry assays, as well as molecular docking analysis combined with site-directed mutagenesis. Results: In our in-house library of old drugs (~1000 compounds), a topical hemostatic and antiseptic 2-hydroxy-3,5-bis[(4-hydroxy-2-methyl-5-sulfophenyl)methyl]-4-methyl-benzene-sulfonic acid (policresulen) was found to be a potent inhibitor of DENV2 NS2B/NS3 protease with IC 50 of 0.48 μg/mL. Furthermore, policresulen inhibited DENV2 replication in BHK-21 cells with IC 50 of 4.99 μg/mL, whereas its IC 50 for cytotoxicity to BHK-21 cells was 459.45 μg/mL. Policresulen acted as a competitive inhibitor of the protease, and slightly affected the protease stability. Using biophysical technology-based assays and molecular docking analysis combined with sitedirected mutagenesis, we demonstrated that the residues Gln106 and Arg133 of DENV2 NS2B/NS3 protease directly interacted with policresulen via hydrogen bonding. Conclusion: Policresulen is a potent inhibitor of DENV2 NS2B/NS3 protease that inhibits DENV2 replication in BHK-21 cells. The binding mode of the protease and policresulen provides useful hints for designing new type of inhibitors against the protease.

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Section: Discussionmentioning

confidence: 99%

Policresulen, a novel NS2B/NS3 protease inhibitor, effectively inhibits the replication of DENV2 virus in BHK-21 cells

Mao

et al. 2015

Acta Pharmacol Sin

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“…VX-950 was prepared at Vertex Pharmaceuticals, Incorporated using a method described previously (46). BILN 2061 was discovered at Boehringer Ingelheim, and its synthesis has been described (7). Human recombinant IFN-␣ was purchased from Calbiochem (La Jolla, CA).…”

Section: Methodsmentioning

confidence: 99%

VX-950, a Novel Hepatitis C Virus (HCV) NS3-4A Protease Inhibitor, Exhibits Potent Antiviral Activities in HCV Replicon Cells

Lin

Perni

Kwong

et al. 2006

Antimicrob Agents Chemother

188

134

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The NS3-4A serine protease of hepatitis C virus (HCV) is essential for viral replication and therefore has been one of the most attractive targets for developing specific antiviral agents against HCV. VX-950, a highly selective, reversible, and potent peptidomimetic inhibitor of the HCV NS3-4A protease, is currently in clinical development for the treatment of hepatitis C. In this report, we describe the in vitro characterization of anti-HCV activities of VX-950 in subgenomic HCV replicon cells. Incubation with VX-950 resulted in a timeand dose-dependent reduction of HCV RNA and proteins in replicon cells. Moreover, following a 2-week incubation with VX-950, a reduction in HCV RNA levels of 4.7 log 10 was observed, and this reduction resulted in elimination of HCV RNA from replicon cells, since there was no rebound in replicon RNA after withdrawal of the inhibitor. The combination of VX-950 and alpha interferon was additive to moderately synergistic in reducing HCV RNA in replicon cells with no significant increase in cytotoxicity. The benefit of the combination was sustained over time: a 4-log 10 reduction in HCV RNA level was achieved following a 9-day incubation with VX-950 and alpha interferon at lower concentrations than when either VX-950 or alpha interferon was used alone. The combination of VX-950 and alpha interferon also suppressed the emergence of in vitro resistance mutations against VX-950 in replicon cells.

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“…Conversion of the quinoline acid to the acid chloride could be accomplished with either thionyl chloride or oxalyl chloride (25). Conversion of the acid halide to the ␣-halo ketone could be accomplished through the diazoketone (1,19,25,26). Treatment of the ␣-halo ketone with sodium borohydride should afford the epoxide (3,29).…”

Section: Methodsmentioning

confidence: 99%

Utility of Alkylaminoquinolinyl Methanols as New Antimalarial Drugs

Dow

Heady

Bhattacharjee

et al. 2006

Antimicrob Agents Chemother

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Mefloquine has been one of the more valuable antimalarial drugs but has never reached its full clinical potential due to concerns about its neurologic side effects, its greater expense than that of other antimalarials, and the emergence of resistance. The commercial development of mefloquine superseded that of another quinolinyl methanol, WR030090, which was used as an experimental antimalarial drug by the U.S. Army in the 1970s. We evaluated a series of related 2-phenyl-substituted alkylaminoquinolinyl methanols (AAQMs) for their potential as mefloquine replacement drugs based on a series of appropriate in vitro and in vivo efficacy and toxicology screens and the theoretical cost of goods. Generally, the AAQMs were less neurotoxic and exhibited greater antimalarial potency, and they are potentially cheaper than mefloquine, but they showed poorer metabolic stability and pharmacokinetics and the potential for phototoxicity. These differences in physiochemical and biological properties are attributable to the "opening" of the piperidine ring of the 4-position side chain. Modification of the most promising compound, WR069878, by substitution of an appropriate N functionality at the 4 position, optimization of quinoline ring substituents at the 6 and 7 positions, and deconjugation of quinoline and phenyl ring systems is anticipated to yield a valuable new antimalarial drug.In the late 1960s to early 1970s, Plasmodium falciparum malaria in Southeast Asia had begun to develop resistance to all of the available antimalarial drugs (6). Cure rates were 11 to 20% and 26 to 50% for chloroquine and quinine, respectively, and had declined to only 90% for the triple combination of quinine/pyrimethamine/dapsone (6). All of these regimens were associated with adverse side effects (6). As a consequence, the U.S. Army began routinely employing two experimental antimalarial drugs, WR030090 and WR033063, for the treatment of recrudescent malaria infections at the Walter Reed Army Medical Center (6). Subsequent field trials demonstrated that WR030090, a quinolinyl methanol, exhibited cure rates of at least 88% and was better tolerated than quinine (6, 21).Shortly thereafter, mefloquine was discovered and was developed commercially by Hoffman La Roche and the U.S. Army. Mefloquine exhibited a long half-life in humans, and this desirable property facilitated its administration as a single dose for malaria treatment and as a once-weekly dosing for prophylaxis (50). In contrast, WR030090 was only partially effective as a prophylactic agent, required a dosing regimen similar to that of quinine to effect cures, and was subsequently abandoned (6,9,21,30). However, it is important to recognize that this occurred because of unfavorable pharmacokinetic characteristics, not as a consequence of unacceptable toxicity.Mefloquine combined with artesunate constitutes one of the most effective combination agents for treatment of malaria (41). Mefloquine is also the only once-weekly drug approved for malaria chemoprophylaxis in the United States that...

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Synthesis of BILN 2061, an HCV NS3 Protease Inhibitor with Proven Antiviral Effect in Humans

Cited by 111 publications

References 30 publications

Policresulen, a novel NS2B/NS3 protease inhibitor, effectively inhibits the replication of DENV2 virus in BHK-21 cells

Policresulen, a novel NS2B/NS3 protease inhibitor, effectively inhibits the replication of DENV2 virus in BHK-21 cells

VX-950, a Novel Hepatitis C Virus (HCV) NS3-4A Protease Inhibitor, Exhibits Potent Antiviral Activities in HCV Replicon Cells

Utility of Alkylaminoquinolinyl Methanols as New Antimalarial Drugs

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