Showing papers by "Pierre L. Beaulieu published in 2004"
TL;DR: Potent analogues in this series inhibit the polymerase at low micromolar concentrations and provide an attractive "drug-like" lead structure for further optimization and the development of potential HCV therapeutics.
111 citations
TL;DR: The synthesis of BILN 2061, an NS3 protease inhibitor with proven antiviral effect in humans, was accomplished in a convergent manner from four building blocks in a suitable manner for preclinical pharmacological evaluation.
104 citations
TL;DR: Optimization of benzimidazole 5-carboxamide derivatives previously identified as specific inhibitors of the NS5B polymerase of the hepatitis C virus has led to the discovery of potent analogues that inhibit the enzyme at low-nanomolar concentrations.
91 citations
TL;DR: The improvement in potency in this ex vivo model of HCV RNA replication validates the mechanism by which this class of allosteric benzimidazole derivatives inhibits the polymerase and represents a significant step forward in the discovery of novel HCV therapeutics.
Abstract: A previously disclosed series of non-nucleoside allosteric inhibitors of the NS5B polymerase of the hepatitis C virus (HCV) was optimized to yield novel compounds with improved physicochemical properties and activity in cell-based assays. Replacement of ionizable carboxylic acids with neutral substituents in lead compounds produced inhibitors with cellular permeability and antiviral activity in a cell-based assay of subgenomic HCV RNA replication (replicon EC(50) as low as 1.7 microM). The improvement in potency in this ex vivo model of HCV RNA replication validates, in part, the mechanism by which this class of allosteric benzimidazole derivatives inhibits the polymerase and represents a significant step forward in the discovery of novel HCV therapeutics.
86 citations
Journal Article•
TL;DR: This review provides a comprehensive account of the progress made towards the discovery of anti-HCV therapeutics based on inhibition of the virally encoded NS5B polymerase, providing validation of the approach for antiviral therapy.
Abstract: The spread of hepatitis C virus (HCV) infections and serious health consequences associated with chronic states of the disease have become a global concern. Small-molecule drugs that are specific for anti-HCV chemotherapy are not available and the current treatments for this disease suffer from limited success. The NS5B RNA-dependent RNA polymerase of HCV is an essential enzyme for viral replication. It has emerged in the last years as the most 'drugable' target of the entire HCV genome. While no agents from this class have yet demonstrated sustained efficacy in infected patients, early stage proof-of-concept has been achieved in the clinic, providing validation of the approach for antiviral therapy. This review provides a comprehensive account of the progress made towards the discovery of anti-HCV therapeutics based on inhibition of the virally encoded NS5B polymerase.
84 citations
TL;DR: The characterization of specific benzimidazole-5-carboxamide-based inhibitors, identified in a screening campaign, revealed that this class of compounds was non-competitive with regard to NTP incorporation and had no effect on processive elongation, but inhibited an initiation phase of the HCV polymerase activity.
Abstract: The interaction of the hepatitis C virus (HCV) RNA-dependent RNA polymerase with RNA substrate is incompletely defined. We have characterized the activities of the HCV NS5B polymerase, modified by different deletions and affinity tags, with a routinely used homopolymeric substrate, and established apparent affinities of the various NS5B constructs both for the NTP and the template/primer substrates. We identified a uniquely tagged HCV NS5B RNA polymerase construct with a lower affinity (higher K(m)) than mature HCV NS5B for template/ primer substrate and highlighted the use of such a polymerase for the identification of inhibitors of NS5B activity, particularly inhibitors of productive RNA binding. The characterization of specific benzimidazole-5-carboxamide-based inhibitors, identified in a screening campaign, revealed that this class of compounds was non-competitive with regard to NTP incorporation and had no effect on processive elongation, but inhibited an initiation phase of the HCV polymerase activity. The potency of these compounds versus a panel of different NS5B polymerase constructs was inversely proportional to the enzymes' affinities for template/primer substrate. The benzimidazole-5-carboxamide compounds also inhibited the full-length, untagged NS5B de novo initiation reaction using HCV 3'-UTR substrate RNA and expand the diversifying pool of potential HCV replication inhibitors.
83 citations
TL;DR: This work has shown clear trends in the determination of inhibition constants in response to known mechanisms, and these trends are consistent with those reported in previous studies of similar mechanisms using EMTs.
Abstract: [*] Dr. S. R. LaPlante, A. Jakalian, N. Aubry, Y. Bousquet, J.-M. Ferland, J. Gillard, S. Lefebvre, M. Poirier, Y. S. Tsantrizos, G. Kukolj, P. L. Beaulieu Departments of Chemistry and Biological Sciences Boehringer Ingelheim (Canada) Ltd., Research and Development 2100 Cunard St., Laval, Quebec (Canada) H7S2G5 Fax: (+1)450-682-8434 E-mail: slaplante@lav.boehringer-ingelheim.com [**] We are grateful to Dr. Michael BBs, Dr. Michael Cordingley, and Dr. Paul Anderson for encouragement and support. We also thank Dr. Timothy Stammers, Dr. Nathalie Goudreau, Dr. Marc-AndrC Poupart, Dr. Dale Cameron, and Mr. Jeff O’Meara for comments or critical reading of the manuscript, as well as Ginette McKercher for determining inhibition constants. Supporting information for this article is available on the WWW under http://www.angewandte.org or from the author. Communications
52 citations
Patent•
05 May 2004TL;DR: In this article, the HCV NS5B polymerase adopts a confirmation in which the finger loop region defined by amino acid residues 18 to 35 is displaced to expose a binding pocket defined generally by amino acids residues 392, 393, 395, 396, 399, 424, 425, 428, 429, 492, 493, 494, 495, 496, 500 and 503.
Abstract: The HCV NS5B polymerase, when complexed with certain inhibitors, adopts a confirmation in which the finger loop region defined by amino acid residues 18 to 35 is displaced to expose a binding pocket defined generally by amino acid residues 392, 393, 395, 396, 399, 424, 425, 428, 429, 492, 493, 494, 495, 496, 500 and 503. This newly exposed binding pocket defines a novel target in the search of further chemical entities which are capable of binding to HCV NS5B and modulating, or preferably inhibiting, the polymerase activity of HCV NS5B.
32 citations
16 citations
TL;DR: This corrects the article to show that the Higgs boson bacterium is a prokaryotic substance, not a “spatially aggregating substance”, which is a type of “plasm” found in the fossil record.
Abstract: Nature 426, 186–189 (2003). In this Letter, the ‘Competing interests statement’ should be corrected to: ‘The authors declare competing financial interests: R.E.S. was the clinical investigator and received an honorarium from Boehringer Ingelheim. All the other authors are or were employees of Boehringer Ingelheim.
8 citations
Patent•
19 Jan 2004
Patent•
19 Jan 2004
TL;DR: An isomer, enantiomer, diastereoisomer or tautomer of a compound, represented by formula (I) wherein A, B, R2, R3, M1, M2, M3, Y1 and Z are as defined in claim 1, or a salt thereof, as an inhibitor of HCV NS5B polymerase as mentioned in this paper.
Abstract: An isomer, enantiomer, diastereoisomer or tautomer of a compound, represented by formula (I) wherein A, B, R2, R3, M1, M2, M3, M4, Y1 and Z are as defined in claim 1, or a salt thereof, as an inhibitor of HCV NS5B polymerase.
Patent•
05 May 2004
TL;DR: The polymerase NS5B du VHC adopte une conformation dans laquelle la region Boucle du doigt definie par les restes d'acide amine 18 a 35 est deplacee de maniere qu'une poche de liaison definie generalement par les other amines, 392, 393, 395, 396, 399, 424, 425, 428 428, 428, 429, 492, 493, 494, 495, 496, 500 and 503 soit exposee.
Abstract: La polymerase NS5B du VHC, lorsqu'elle est complexee avec certains inhibiteurs, adopte une conformation dans laquelle la region boucle du doigt definie par les restes d'acide amine 18 a 35 est deplacee de maniere qu'une poche de liaison definie generalement par les restes d'acide amines, 392, 393, 395, 396, 399, 424, 425, 428, 429, 492, 493, 494, 495, 496, 500 et 503 soit exposee. Cette poche recemment exposee definit une nouvelle cible dans la recherche d'autres entites chimiques capables de se lier a NS5B du VHC et de moduler ou de preference d'inhiber l'activite de polymerase de NS5B de VHC.