Pierre Raboisson

Publications (38)170.14 Total impact

• Article: TMC647055, a potent nonnucleoside hepatitis C virus NS5B polymerase inhibitor with cross-genotypic coverage.

  Benoit Devogelaere, Jan Martin Berke, Leen Vijgen, Pascale Dehertogh, Els Fransen, Erna Cleiren, Liesbet van der Helm, Origène Nyanguile, Abdellah Tahri, Katie Amssoms, Oliver Lenz, Maxwell D Cummings, Reginald F Clayton, Sandrine Vendeville, Pierre Raboisson, Kenneth A Simmen, Gregory C Fanning, Tse-I Lin
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  ABSTRACT: Hepatitis C virus (HCV) infection is a major global health burden and is associated with an increased risk of liver cirrhosis and hepatocellular carcinoma. There remains an unmet medical need for efficacious and safe direct antivirals with complementary modes of action for combination in treatment regimens to deliver a high cure rate with a short duration of treatment for HCV patients. Here we report the in vitro inhibitory activity, mode of action, binding kinetics, and resistance profile of TMC647055, a novel and potent nonnucleoside inhibitor of the HCV NS5B RNA-dependent RNA polymerase. In vitro combination studies with an HCV NS3/4A protease inhibitor demonstrated potent suppression of HCV RNA replication, confirming the potential for combination of these two classes in the treatment of chronic HCV infection. TMC647055 is a potent nonnucleoside NS5B polymerase inhibitor of HCV replication with a promising in vitro biochemical, kinetic, and virological profile that is currently undergoing clinical evaluation.
  Antimicrobial Agents and Chemotherapy 06/2012; 56(9):4676-84. · 4.84 Impact Factor
• Article: Finger loop inhibitors of the HCV NS5b polymerase. Part II. Optimization of tetracyclic indole-based macrocycle leading to the discovery of TMC647055.

  Sandrine Vendeville, Tse-I Lin, Lili Hu, Abdellah Tahri, David McGowan, Maxwell D Cummings, Katie Amssoms, Maxime Canard, Stefaan Last, Iris Van den Steen, [......], Jan Martin Berke, Pascale Dehertogh, Els Fransen, Erna Cleiren, Liesbet van der Helm, Gregory Fanning, Kristof Van Emelen, Origène Nyanguile, Kenny Simmen, Pierre Raboisson
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  ABSTRACT: Optimization of a novel series of macrocyclic indole-based inhibitors of the HCV NS5b polymerase targeting the finger loop domain led to the discovery of lead compounds exhibiting improved potency in cellular assays and superior pharmacokinetic profile. Further lead optimization performed on the most promising unsaturated-bridged subseries provided the clinical candidate 27-cyclohexyl-12,13,16,17-tetrahydro-22-methoxy-11,17-dimethyl-10,10-dioxide-2,19-methano-3,7:4,1-dimetheno-1H,11H-14,10,2,9,11,17-benzoxathiatetraazacyclo docosine-8,18(9H,15H)-dione, TMC647055 (compound 18a). This non-zwitterionic 17-membered ring macrocycle combines nanomolar cellular potency (EC(50) of 82 nM) with minimal associated cell toxicity (CC(50)>20 μM) and promising pharmacokinetic profiles in rats and dogs. TMC647055 is currently being evaluated in the clinic.
  Bioorganic & medicinal chemistry letters 04/2012; 22(13):4437-43. · 2.65 Impact Factor
• Article: Finger-loop inhibitors of the HCV NS5b polymerase. Part 1: Discovery and optimization of novel 1,6- and 2,6-macrocyclic indole series.

  David McGowan, Sandrine Vendeville, Tse-I Lin, Abdellah Tahri, Lili Hu, Maxwell D Cummings, Katie Amssoms, Jan Martin Berke, Maxime Canard, Erna Cleiren, [......], Els Fransen, Elisabeth Van Der Helm, Iris Van den Steen, Leen Vijgen, Marie-Claude Rouan, Gregory Fanning, Origène Nyanguile, Kristof Van Emelen, Kenneth Simmen, Pierre Raboisson
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  ABSTRACT: Novel conformationaly constrained 1,6- and 2,6-macrocyclic HCV NS5b polymerase inhibitors, in which either the nitrogen or the phenyl ring in the C2 position of the central indole core is tethered to an acylsulfamide acid bioisostere, have been designed and tested for their anti-HCV potency. This transformational route toward non-zwitterionic finger loop-directed inhibitors led to the discovery of derivatives with improved cell potency and pharmacokinetic profile.
  Bioorganic & medicinal chemistry letters 04/2012; 22(13):4431-6. · 2.65 Impact Factor
• Article: Structure-based macrocyclization yields hepatitis C virus NS5B inhibitors with improved binding affinities and pharmacokinetic properties.

  Maxwell D Cummings, Tse-I Lin, Lili Hu, Abdellah Tahri, David McGowan, Katie Amssoms, Stefaan Last, Benoit Devogelaere, Marie-Claude Rouan, Leen Vijgen, [......], Pascale Dehertogh, Els Fransen, Erna Cleiren, Liesbet van der Helm, Gregory Fanning, Kristof Van Emelen, Origène Nyanguile, Kenny Simmen, Pierre Raboisson, Sandrine Vendeville
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  ABSTRACT: The concept of drug-likeness distills the physicochemical properties of small-molecule drugs to a set of rules. Macrocyclic drugs are known to break these rules. A structure-based macrocyclization strategy was applied to design new hepatitis C virus NS5B inhibitors with improved pharmocokinetic properties, exemplifying a rational strategy for overcoming the confines of standard "drug-like chemical space".
  Angewandte Chemie International Edition 03/2012; 51(19):4637-40. · 13.45 Impact Factor
• Source

  Available from: Christian Sund

  Article: Discovery of 4'-azido-2'-deoxy-2'-C-methyl cytidine and prodrugs thereof: a potent inhibitor of Hepatitis C virus replication.

  Magnus Nilsson, Genadiy Kalayanov, Anna Winqvist, Pedro Pinho, Christian Sund, Xiao-Xiong Zhou, Horst Wähling, Anna-Karin Belfrage, Michael Pelcman, Tatiana Agback, [......], Herman de Kock, David B Smith, Joseph A Martin, Klaus Klumpp, Kenneth Simmen, Lotta Vrang, Ylva Terelius, Bertil Samuelsson, Sa Rosenquist, Nils Gunnar Johansson
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  ABSTRACT: 4'-Azido-2'-deoxy-2'-methylcytidine (14) is a potent nucleoside inhibitor of the HCV NS5B RNA-dependent RNA polymerase, displaying an EC(50) value of 1.2 μM and showing moderate in vivo bioavailability in rat (F=14%). Here we describe the synthesis and biological evaluation of 4'-azido-2'-deoxy-2'-methylcytidine and prodrug derivatives thereof.
  Bioorganic & medicinal chemistry letters 03/2012; 22(9):3265-8. · 2.65 Impact Factor
• Article: Antiviral activity and mode of action of TMC647078, a novel nucleoside inhibitor of the hepatitis C virus NS5B polymerase.

  Jan Martin Berke, Leen Vijgen, Sophie Lachau-Durand, Megan H Powdrill, Svea Rawe, Elena Sjuvarsson, Staffan Eriksson, Matthias Götte, Els Fransen, Pascale Dehertogh, Christel Van den Eynde, Laurent Leclercq, Tim H M Jonckers, Pierre Raboisson, Magnus Nilsson, Bertil Samuelsson, Åsa Rosenquist, Gregory C Fanning, Tse-I Lin
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  ABSTRACT: Chronic infection with hepatitis C virus (HCV) is a major global health burden and is associated with an increased risk of liver cirrhosis and hepatocellular carcinoma. Current therapy for HCV infection has limited efficacy, particularly against genotype 1 virus, and is hampered by a range of adverse effects. Therefore, there is a clear unmet medical need for efficacious and safe direct antiviral drugs for use in combination with current treatments to increase cure rates and shorten treatment times. The broad genotypic coverage achievable with nucleosides or nucleotides and the high genetic barrier to resistance of these compounds observed in vitro and in vivo suggest that this class of inhibitors could be a valuable component of future therapeutic regimens. Here, we report the in vitro inhibitory activity and mode of action of 2'-deoxy-2'-spirocyclopropylcytidine (TMC647078), a novel and potent nucleoside inhibitor of the HCV NS5B RNA-dependent RNA polymerase that causes chain termination of the nascent HCV RNA chain. In vitro combination studies with a protease inhibitor resulted in additive efficacy in the suppression of HCV RNA replication, highlighting the potential for the combination of these two classes in the treatment of chronic HCV infection. No cytotoxic effects were observed in various cell lines. Biochemical studies indicated that TMC647078 is phosphorylated mainly by deoxycytidine kinase (dCK) without inhibiting the phosphorylation of the natural substrate, and high levels of triphosphate were observed in Huh7 cells and in primary hepatocytes in vitro. TMC647078 is a potent novel nucleoside inhibitor of HCV replication with a promising in vitro virology and biology profile.
  Antimicrobial Agents and Chemotherapy 05/2011; 55(8):3812-20. · 4.84 Impact Factor
• Article: Practical synthesis of (2'R)-2'-deoxy-2'-C-methyluridine by highly diastereoselective homogeneous hydrogenation.

  Sébastien Lemaire, Ioannis Houpis, Rainer Wechselberger, Jaak Langens, Wim A A Vermeulen, Nico Smets, Ulrike Nettekoven, Youchu Wang, Tingting Xiao, Haisheng Qu, Renmao Liu, Tim H M Jonckers, Pierre Raboisson, Koen Vandyck, Karl M Nilsson, Vittorio Farina
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  ABSTRACT: Diastereoselective hydrogenation of 2'-deoxy-2'-exo-methyleneuridine was carried out under homogeneous conditions using a low loading of a chiral Rh catalyst. This, coupled with improvements in the synthesis of the substrate, allowed the smooth pilot plant preparation of the title compound on >10 kg scale.
  The Journal of Organic Chemistry 01/2011; 76(1):297-300. · 4.45 Impact Factor
• Source

  Available from: Christian Sund

  Article: 2'-Deoxy-2'-spirocyclopropylcytidine revisited: a new and selective inhibitor of the hepatitis C virus NS5B polymerase.

  Tim H M Jonckers, Tse-I Lin, Christophe Buyck, Sophie Lachau-Durand, Koen Vandyck, Steven Van Hoof, Leen A M Vandekerckhove, Lili Hu, Jan Martin Berke, Leen Vijgen, [......], Herman de Kock, Magnus Nilsson, Christian Sund, Christina Rydegård, Bertil Samuelsson, Asa Rosenquist, Gregory Fanning, Kristof Van Emelen, Kenneth Simmen, Pierre Raboisson
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  ABSTRACT: The current therapy for hepatitis C virus (HCV) infection has limited efficacy, in particular against the genotype 1 virus, and a range of side effects. In this context of high unmet medical need, more efficacious drugs targeting HCV nonstructural proteins are of interest. Here we describe 2'-deoxy-2'-spirocyclopropylcytidine (5) as a new inhibitor of the HCV NS5B RNA-dependent RNA polymerase, displaying an EC(50) of 7.3 μM measured in the Huh7-Rep cell line and no associated cytotoxicity (CC(50) > 98.4 μM). Computational results indicated high similarity between 5 and related HCV inhibiting nucleosides. A convenient synthesis was devised, facilitating synthesis of multigram quantities of 5. As the exposure measured after oral administration of 5 was found to be limited, the 3'-mono- and 3',5'-diisobutyryl ester prodrugs 20 and 23, respectively, were evaluated. The oral dosing of 23 led to substantially increased exposure to 5 in both rats and dogs.
  Journal of Medicinal Chemistry 10/2010; 53(22):8150-60. · 4.80 Impact Factor
• Article: Synthesis and SAR of potent inhibitors of the Hepatitis C virus NS3/4A protease: exploration of P2 quinazoline substituents.

  Magnus Nilsson, Anna Karin Belfrage, Stefan Lindström, Horst Wähling, Charlotta Lindquist, Susana Ayesa, Pia Kahnberg, Mikael Pelcman, Kurt Benkestock, Tatiana Agback, [......], Christina Rydergård, Michael Edlund, Anders Eneroth, Pierre Raboisson, Tse-I Lin, Herman de Kock, Piet Wigerinck, Kenneth Simmen, Bertil Samuelsson, Sa Rosenquist
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  ABSTRACT: Novel NS3/4A protease inhibitors comprising quinazoline derivatives as P2 substituent were synthesized. High potency inhibitors displaying advantageous PK properties have been obtained through the optimization of quinazoline P2 substituents in three series exhibiting macrocyclic P2 cyclopentane dicarboxylic acid and P2 proline urea motifs. For the quinazoline moiety it was found that 8-methyl substitution in the P2 cyclopentane dicarboxylic acid series improved on the metabolic stability in human liver microsomes. By comparison, the proline urea series displayed advantageous Caco-2 permeability over the cyclopentane series. Pharmacokinetic properties in vivo were assessed in rat on selected compounds, where excellent exposure and liver-to-plasma ratios were demonstrated for a member of the 14-membered quinazoline substituted P2 proline urea series.
  Bioorganic & medicinal chemistry letters 07/2010; 20(14):4004-11. · 2.65 Impact Factor
• Article: Corrigendum: Induced-Fit Binding of the Macrocyclic Noncovalent Inhibitor TMC435 to its HCV NS3/NS4A Protease Target.

  Maxwell D Cummings, Jimmy Lindberg, Tse-I Lin, Herman de Kock, Oliver Lenz, Elisabet Lilja, Sara Felländer, Vera Baraznenok, Susanne Nyström, Magnus Nilsson, Lotta Vrang, Michael Edlund, Asa Rosenquist, Bertil Samuelsson, Pierre Raboisson, Kenneth Simmen
  Angewandte Chemie International Edition 04/2010; 49(19):3250. · 13.45 Impact Factor
• Article: 1a/1b subtype profiling of nonnucleoside polymerase inhibitors of hepatitis C virus.

  Origène Nyanguile, Benoit Devogelaere, Leen Vijgen, Walter Van den Broeck, Frederik Pauwels, Maxwell D Cummings, Hendrik L De Bondt, Ann M Vos, Jan M Berke, Oliver Lenz, [......], Wendy Mostmans, Pascale Dehertogh, Frédéric Delouvroy, Sandrine Vendeville, Koen VanDyck, Koen Dockx, Erna Cleiren, Pierre Raboisson, Kenneth A Simmen, Gregory C Fanning
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  ABSTRACT: The RNA-dependent RNA polymerase (NS5B) of hepatitis C virus (HCV) is an unusually attractive target for drug discovery since it contains five distinct drugable sites. The success of novel antiviral therapies will require nonnucleoside inhibitors to be active in at least patients infected with HCV of subtypes 1a and 1b. Therefore, the genotypic assessment of these agents against clinical isolates derived from genotype 1-infected patients is an important prerequisite for the selection of suitable candidates for clinical development. Here we report the 1a/1b subtype profiling of polymerase inhibitors that bind at each of the four known nonnucleoside binding sites. We show that inhibition of all of the clinical isolates tested is maintained, except for inhibitors that bind at the palm-1 binding site. Subtype coverage varies across chemotypes within this class of inhibitors, and inhibition of genotype 1a improves when hydrophobic contact with the polymerase is increased. We investigated if the polymorphism of the palm-1 binding site is the sole cause of the reduced susceptibility of subtype 1a to inhibition by 1,5-benzodiazepines by using reverse genetics, X-ray crystallography, and surface plasmon resonance studies. We showed Y415F to be a key determinant in conferring resistance on subtype 1a, with this effect being mediated through an inhibitor- and enzyme-bound water molecule. Binding studies revealed that the mechanism of subtype 1a resistance is faster dissociation of the inhibitor from the enzyme.
  Journal of Virology 03/2010; 84(6):2923-34. · 5.40 Impact Factor
• Article: Inside Cover: Induced-Fit Binding of the Macrocyclic Noncovalent Inhibitor TMC435 to its HCV NS3/NS4A Protease Target (Angew. Chem. Int. Ed. 9/2010).

  Maxwell D Cummings, Jimmy Lindberg, Tse-I Lin, Herman de Kock, Oliver Lenz, Elisabet Lilja, Sara Felländer, Vera Baraznenok, Susanne Nyström, Magnus Nilsson, Lotta Vrang, Michael Edlund, Asa Rosenquist, Bertil Samuelsson, Pierre Raboisson, Kenneth Simmen
  Angewandte Chemie International Edition 02/2010; 49(9):1510. · 13.45 Impact Factor
• Article: In vitro resistance profile of the hepatitis C virus NS3/4A protease inhibitor TMC435.

  Oliver Lenz, Thierry Verbinnen, Tse-I Lin, Leen Vijgen, Maxwell D Cummings, Jimmy Lindberg, Jan Martin Berke, Pascale Dehertogh, Els Fransen, Annick Scholliers, Katrien Vermeiren, Tania Ivens, Pierre Raboisson, Michael Edlund, Susan Storm, Lotta Vrang, Herman de Kock, Gregory C Fanning, Kenneth A Simmen
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  ABSTRACT: TMC435 is a small-molecule inhibitor of the NS3/4A serine protease of hepatitis C virus (HCV) currently in phase 2 development. The in vitro resistance profile of TMC435 was characterized by selection experiments with HCV genotype 1 replicon cells and the genotype 2a JFH-1 system. In 80% (86/109) of the sequences from genotype 1 replicon cells analyzed, a mutation at NS3 residue D168 was observed, with changes to V or A being the most frequent. Mutations at NS3 positions 43, 80, 155, and 156, alone or in combination, were also identified. A transient replicon assay confirmed the relevance of these positions for TMC435 inhibitory activity. The change in the 50% effective concentrations (EC(50)s) observed for replicons with mutations at position 168 ranged from <10-fold for those with the D168G or D168N mutation to approximately 2,000-fold for those with the D168V or D168I mutation, compared to the EC(50) for the wild type. Of the positions identified, mutations at residue Q80 had the least impact on the activity of TMC435 (<10-fold change in EC(50)s), while greater effects were observed for some replicons with mutations at positions 43, 155, and 156. TMC435 remained active against replicons with the specific mutations observed after in vitro or in vivo exposure to telaprevir or boceprevir, including most replicons with changes at positions 36, 54, and 170 (<3-fold change in EC(50)s). Replicons carrying mutations affecting the activity of TMC435 remained fully susceptible to alpha interferon and NS5A and NS5B inhibitors. Finally, combinations of TMC435 with alpha interferon and NS5B polymerase inhibitors prevented the formation of drug-resistant replicon colonies.
  Antimicrobial Agents and Chemotherapy 02/2010; 54(5):1878-87. · 4.84 Impact Factor
• Article: Induced-fit binding of the macrocyclic noncovalent inhibitor TMC435 to its HCV NS3/NS4A protease target.

  Maxwell D Cummings, Jimmy Lindberg, Tse-I Lin, Herman de Kock, Oliver Lenz, Elisabet Lilja, Sara Felländer, Vera Baraznenok, Susanne Nyström, Magnus Nilsson, Lotta Vrang, Michael Edlund, Asa Rosenquist, Bertil Samuelsson, Pierre Raboisson, Kenneth Simmen
  Angewandte Chemie International Edition 02/2010; 49(9):1652-5. · 13.45 Impact Factor
• Article: Structure-based design of a benzodiazepine scaffold yields a potent allosteric inhibitor of hepatitis C NS5B RNA polymerase.

  Koen Vandyck, Maxwell D Cummings, Origène Nyanguile, Carlo W Boutton, Sandrine Vendeville, David McGowan, Benoit Devogelaere, Katie Amssoms, Stefaan Last, Klara Rombauts, Abdellah Tahri, Pedro Lory, Lili Hu, Derek A Beauchamp, Kenny Simmen, Pierre Raboisson
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  ABSTRACT: HCV NS5B polymerase, an essential and virus-specific enzyme, is an important target for drug discovery. Using structure-based design, we optimized a 1,5-benzodiazepine NS5B polymerase inhibitor chemotype into a new sulfone-containing scaffold. The design yielded potent inhibitor (S)-4c (K(D) = 0.79 nM), which has approximately 20-fold greater affinity for NS5B than its carbonyl analogue (R)-2c.
  Journal of Medicinal Chemistry 07/2009; 52(14):4099-102. · 4.80 Impact Factor
• Article: 1,5-Benzodiazepine inhibitors of HCV NS5B polymerase.

  David McGowan, Origène Nyanguile, Maxwell D Cummings, Sandrine Vendeville, Koen Vandyck, Walter Van den Broeck, Carlo W Boutton, Hendrik De Bondt, Ludo Quirynen, Katie Amssoms, [......], Erna Cleiren, Wendy Mostmans, Pedro Lory, Geert Pille, Kristof Van Emelen, Gregory Fanning, Frederik Pauwels, Tse-I Lin, Kenneth Simmen, Pierre Raboisson
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  ABSTRACT: Optimization through parallel synthesis of a novel series of hepatitis C virus (HCV) NS5B polymerase inhibitors led to the identification of (R)-11-(4-benzyloxy-2-fluorophenyl)-6-hydroxy-3,3-dimethyl-10-(6-methylpyridine-2-carbonyl)-2,3,4,5,10,11-hexahydro-dibenzo[b,e][1,4]diazepin-1-one 11zc and (R)-11-(4-benzyloxy-2-fluorophenyl)-6-hydroxy-3,3-dimethyl-10-(2,5-dimethyloxazol-4-carbonyl)-2,3,4,5,10,11-hexahydro-dibenzo[b,e][1,4]diazepin-1-one 11zk as potent (replicon EC(50)=400nM and 270nM, respectively) and selective (CC(50)>20muM) inhibitors of HCV replication. These data warrant further lead-optimization efforts.
  Bioorganic & medicinal chemistry letters 03/2009; 19(9):2492-6. · 2.65 Impact Factor
• Article: In vitro activity and preclinical profile of TMC435350, a potent hepatitis C virus protease inhibitor.

  Tse-I Lin, Oliver Lenz, Gregory Fanning, Thierry Verbinnen, Frédéric Delouvroy, Annick Scholliers, Katrien Vermeiren, Asa Rosenquist, Michael Edlund, Bertil Samuelsson, Lotta Vrang, Herman de Kock, Piet Wigerinck, Pierre Raboisson, Kenneth Simmen
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  ABSTRACT: The hepatitis C virus (HCV) NS3/4A serine protease has been explored as a target for the inhibition of viral replication in preclinical models and in HCV-infected patients. TMC435350 is a highly specific and potent inhibitor of NS3/4A protease selected from a series of novel macrocyclic inhibitors. In biochemical assays using NS3/4A proteases of genotypes 1a and 1b, inhibition constants of 0.5 and 0.4 nM, respectively, were determined. TMC435350 inhibited HCV replication in a cellular assay (subgenomic 1b replicon) with a half-maximal effective concentration (EC(50)) of 8 nM and a selectivity index of 5,875. The compound was synergistic with alpha interferon and an NS5B inhibitor in the replicon model and additive with ribavirin. In rats, TMC435350 was extensively distributed to the liver and intestinal tract (tissue/plasma area under the concentration-time curve ratios of >35), and the absolute bioavailability was 44% after a single oral administration. Compound concentrations detected in both plasma and liver at 8 h postdosing were above the EC(99) value measured in the replicon. In conclusion, given the selective and potent in vitro anti-HCV activity, the potential for combination with other anti-HCV agents, and the favorable pharmacokinetic profile, TMC435350 has been selected for clinical development.
  Antimicrobial Agents and Chemotherapy 02/2009; 53(4):1377-85. · 4.84 Impact Factor
• Article: Discovery of novel, potent and bioavailable proline-urea based macrocyclic HCV NS3/4A protease inhibitors.

  Sandrine Vendeville, Magnus Nilsson, Herman de Kock, Tse-I Lin, Dmitry Antonov, Björn Classon, Susana Ayesa, Vladimir Ivanov, Per-Ola Johansson, Pia Kahnberg, [......], Oliver Lenz, Frederic Delouvroy, Marleen Van Dooren, Natalie Kindermans, Dominique Surleraux, Piet Wigerinck, Asa Rosenquist, Bertil Samuelsson, Kenneth Simmen, Pierre Raboisson
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  ABSTRACT: A novel series of P3-truncated macrocyclic HCV NS3/4A protease inhibitors containing a P2 proline-urea or carbamate scaffold was synthesized. Very potent inhibitors were obtained through the optimization of the macrocycle size, urea and proline substitution, and bioisosteric replacement of the P1 carboxylic acid moiety. Variation of the lipophilicity by introduction of small lipophilic substituents resulted in improved PK profiles, ultimately leading to compound 13Bh, an extremely potent (K(i)=0.1 nM, EC(50)=4.5 nM) and selective (CC(50) (Huh-7 cells)>50 microM) inhibitor, displaying an excellent PK profile in rats characterized by an oral bioavailability of 54% and a high liver exposure after oral administration.
  Bioorganic & medicinal chemistry letters 12/2008; 18(23):6189-93. · 2.65 Impact Factor
• Article: 1,5-benzodiazepines, a novel class of hepatitis C virus polymerase nonnucleoside inhibitors.

  Origène Nyanguile, Frederik Pauwels, Walter Van den Broeck, Carlo W Boutton, Ludo Quirynen, Tania Ivens, Liesbet van der Helm, Geneviève Vandercruyssen, Wendy Mostmans, Frédéric Delouvroy, Pascale Dehertogh, Maxwell D Cummings, Jean-Francois Bonfanti, Kenneth A Simmen, Pierre Raboisson
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  ABSTRACT: The exogenous control of hepatitis C virus (HCV) replication can be mediated through the inhibition of the RNA-dependent RNA polymerase (RdRp) activity of NS5B. Small-molecule inhibitors of NS5B include nucleoside and nonnucleoside analogs. Here, we report the discovery of a novel class of HCV polymerase nonnucleoside inhibitors, 1,5-benzodiazepines (1,5-BZDs), identified by high-throughput screening of a library of small molecules. A fluorescence-quenching assay and X-ray crystallography revealed that 1,5-BZD 4a bound stereospecifically to NS5B next to the catalytic site. When introduced into replicons, mutations known to confer resistance against chemotypes that bind at this site were detrimental to inhibition by 1,5-BZD 7a. Using a panel of enzyme isolates that covered genotypes 1 to 6, we showed that compound 4a inhibited genotype 1 only. In mechanistic studies, 4a was found to inhibit the RdRp activity of NS5B noncompetitively with GTP and to inhibit the formation of the first phosphodiester bond during the polymerization cycle. The specificity for the HCV target was evaluated by profiling the 1,5-BZDs against other viral and human polymerases, as well as BZD receptors.
  Antimicrobial Agents and Chemotherapy 11/2008; 52(12):4420-31. · 4.84 Impact Factor
• Article: Structure-activity relationship study on a novel series of cyclopentane-containing macrocyclic inhibitors of the hepatitis C virus NS3/4A protease leading to the discovery of TMC435350.

  Pierre Raboisson, Herman de Kock, Asa Rosenquist, Magnus Nilsson, Lourdes Salvador-Oden, Tse-I Lin, Natalie Roue, Vladimir Ivanov, Horst Wähling, Kristina Wickström, [......], Abdellah Tahri, Lili Hu, Carlo Boutton, Oliver Lenz, Frederic Delouvroy, Geert Pille, Dominique Surleraux, Piet Wigerinck, Bertil Samuelsson, Kenneth Simmen
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  ABSTRACT: SAR analysis performed with a limited set of cyclopentane-containing macrocycles led to the identification of N-[17-[2-(4-isopropylthiazole-2-yl)-7-methoxy-8-methylquinolin-4-yloxy]-13-methyl-2,14-dioxo-3,13-diazatricyclo [13.3.0.0(4,6)]octadec-7-ene-4-carbonyl](cyclopropyl)sulfonamide (TMC435350, 32c) as a potent inhibitor of HCV NS3/4A protease (K(i)=0.36nM) and viral replication (replicon EC(50)=7.8nM). TMC435350 also displayed low in vitro clearance and high permeability, which were confirmed by in vivo pharmacokinetic studies. TMC435350 is currently being evaluated in the clinics.
  Bioorganic & medicinal chemistry letters 10/2008; 18(17):4853-8. · 2.65 Impact Factor