MONDAY, APRIL 28
7:15 am Registration and Morning Coffee
HEPATITIS C VIRUS POLYMERASE
INHIBITORS IN DEVELOPMENT
8:00 Chairperson’s Opening Remarks
Chris McGuigan, Ph.D., Professor of Medicinal Chemistry, Welsh School of Pharmacy, Cardiff University, UK
8:15 Structure-Based Design of Non-Nucleoside NS5B Inhibitors for the Treatment of HCV
R. Than Hendricks, Ph.D., Principal Research Scientist, Medicinal Chemistry, Roche Palo Alto
The discovery and optimization of two novel series of HCV NS5B polymerase inhibitors will be discussed. Both series were shown to bind in the same region of NS5B using X-ray crystallography. This presentation will highlight the different strategies that were utilized in the optimization of both potency and physical properties.
8:45 Benzothiadiazine Hepatitis C NS5B Polymerase Inhibitors
Douglas K. Hutchinson, Ph.D., Research Investigator, Antiviral Research, Global Pharmaceutical Research and Development, Abbott Laboratories
4,4-Dialkyl-1-hydroxy-3-oxo-3.4-dihydronaphthalene-1-yl benzothiadiazine derivatives were synthesized and evaluated as inhibitors of genotypes 1a and 1b hepatitis C (HCV) NS5B polymerase. A number of these compounds exhibited extremely potent activity against genotypes 1a and 1b polymerase in both enzymatic and cell culture assays. Several representative examples showed favorable pharmacokinetic behavior in the rat, and one compound was found to affect a ca. 2 log reduction in viral load in a HCV-infected chimpanzee.
9:15 R7128, A Potent and Selective Nucleoside Inhibitor of HCV NS5B Polymerase: An Overview of Clinical Efficacy and Progress toward Second-Generation Inhibitors
Michael J. Sofia, Ph.D., Vice President Chemistry, Pharmasset, Inc.
R7128, a pro-drug of PSI-6130, (ß-D-2’-Deoxy-2’-fluoro-2’-C-methylcytidine), is currently in clinical development for the treatment of chronic hepatitis C. R7128 has demonstrated potent clinical efficacy and safety in a 14-day monotherapy study and in a 28-day study in combination with interferon (Pegasys) plus ribavirin (Copegus). Rapid virological response (RVR) was achieved in 85% of patients receiving 1500 mg bid R7128 in combination with Pegasys and Copegus with a mean -5.12log10 viral load drop at 15 days. Subsequent efforts to develop a second-generation liver-targeting nucleoside HCV inhibitor have led to a series of compounds with enhanced potency and desirable development characteristics. Data on R7128 and an overview of our second-generation compounds will be presented.
9:45 Networking Coffee Break
10:15 Potent and Selective Anti-HCV Nucleotide Pro-Drugs
Chris McGuigan, Ph.D., Professor of Medicinal Chemistry, Welsh School of Pharmacy, Cardiff University, UK
Many nucleosides are effective against isolated viral polymerases as their triphosphate forms, and yet inactive against the virus as the administered nucleoside, due to poor host kinase-mediated phosphorylation. Our ProTide (phosphate pro-drug) approach addresses this by enabling the intracellular delivery of charged bio-active nucleotides, administered as their un-charged masked phosphate pro-drugs. Data have been published by us, in collaboration with Roche Palo Alto, on the inactive nucleoside 4’-AZU. Other examples will be presented.
10:45 Novel Carbon-linked Dihydropyrones as Allosteric Inhibitors of HCV RNA-Dependent RNA Polymerase
Hui Li, Ph.D., Senior Principal Scientist, Discovery Chemistry, Pfizer Global Research & Development
A novel class of dihydropyrones has been identified as potent and selective allosteric HCV NS5B polymerase inhibitors. Replacement of the sulfur linker atom with carbon reduced compound acidity and greatly increased its cell permeation. Further structure activity relationship (SAR) studies had led to the identification of compounds with significantly improved potency in the cell-based replicon assay and favorable pharmacokinetic profile.
11:15 Design and Optimization of Acylpyrrolidine Inhibitors of HCV Polymerase
Richard L. Jarvest, D.Phil., Director, Infectious Diseases Centre of Excellence in Drug Discovery, GlaxoSmithKline
The viral RNA-dependent RNA polymerase, encoded by the HCV NS5B gene, is obligatory for virus replication. The enzyme displays several distinct small-molecule inhibitor binding sites, making it an attractive target for therapeutic intervention, with the added prospect of complementary resistance profiles for different inhibitor classes. This presentation will focus on the acylpyrrolidine series of inhibitors.
11:45 Technology Watch (Sponsorship Available)
12:00 pm Luncheon Technology Workshop
(Sponsorship Available) or Lunch on Your Own
1:00 Break
HEPATITIS C VIRUS PROTEASE INHIBITORS
IN DEVELOPMENT
1:25 Chairperson’s Remarks
Flossie Wong-Staal, Ph.D., CSO, Executive Vice President Research, ItherX Pharmaceuticals, Inc.
1:30 Structure-Based Design and Optimization of the HCV NS3/4A Protease Inhibitor SCH503034
Zhuyan Guo, Ph.D., Principal Scientist, Chemistry, Schering-Plough Research Institute
Starting from an undecapeptide substrate, a peptidic ketoamide inhibitor was identified. Structure-based drug design was carried out to truncate and improve the inhibitor, which led to the discovery of SCH503034, a tripeptide ketoamide inhibitor with a Ki* value of 14 nM, good bioavailability, and low toxicity. SCH503034 is currently in Phase II clinical trials.
2:00 Discovery of the Macrocyclic HCV Protease Inhibitor TMC435350
Pierre Raboisson, Ph.D., HCV Disease Area Chemistry Leader, Tibotec BVBA
Lead optimization of a novel series of cyclopentane-containing macrocyclic NS3/4A serine protease inhibitors resulted in the discovery of the clinical candidate TMC435350, a potent and selective inhibitor of HCV replication in genotype 1b replicon cells with an EC50 value of 8 nM. The selectivity index (SI) was over 2000 in a panel of different cell lines as well as in a representative panel of RNA and DNA viruses. The binding mode of TMC435350 to the HCV protease was confirmed by X-ray crystallography analysis of TMC435350 bound to NS3. Furthermore, TMC435350 exhibited a synergistic effect with interferon-α (IFN-α) in reducing HCV replicon RNA and in suppressing the emergence of drug-resistant replicon colonies. Pharmacokinetic and safety pharmacology assessment prompted the selection of TMC435350 as the lead candidate currently being evaluated in a Phase II clinical trial in HCV-infected patients.
2:30 Discovery of MK-7009: A Novel Macrocyclic Inhibitor of HCV NS3/4A Protease
Michael T. Rudd, Ph.D., Research Fellow, Medicinal Chemistry, Merck Research Laboratories
The current standard of care for HCV infection is treatment with pegylated interferon alpha in combination with ribavirin, however, this regimen results in limited efficacy and significant side effects. Efforts toward improved HCV treatment include the development of direct antiviral agents that inhibit key steps in the viral replication process. One such target is the HCV NS3/4A protease. Our interest has been in identifying novel HCV NS3/4A protease inhibitors with good enzyme potency, cellular activity, and liver exposure. Toward this goal, initial targets were designed using molecular modeling. The development and optimization of lead compounds along with the profile of clinical candidate MK-7009 will be presented.
3:00 Technology Watch (Sponsorship Available)
3:15 Networking Refreshment Break, Poster and Exhibit Viewing
4:00 Discovery of ITMN-191: A Potent and Selective Inhibitor of HCV NS3/4A Serine Protease Now in Clinical Development
Leonid Beigelman, Ph.D., Vice President, Medicinal Chemistry, InterMune
The standard of care for chronic HCV infection, weekly injection of pegylated interferon and twice daily orally administered ribavirin, achieves sustained viral response in approximately 50% of all patients. Even lower cure rates are reported in certain subpopulations such as those infected with HCV genotype 1, those with a high viral load, or African Americans. Consequently, there is an urgent need to discover novel potent and specific HCV antiviral agents. In the last decade, the NS3/4A serine protease of HCV has emerged as a key target with clinical validation. We will present the discovery of ITMN-191, a potent and selective inhibitor of NS3/4A, which is now under clinical studies.
4:30 Speaker to Be Announced
5:00 Targeting Induced-Fit Viral Proteases for Antiviral Chemotherapy: Discovery of Allosteric Inhibitors of Hepatitis C Virus NS3/NS4A Heterocomplex Serine Protease
François Jean, Ph.D.; Associate Professor, Department of Microbiology and Immunology; Scientific Director, Centre for Disease Modeling BCL-3 Facility; The University of British Columbia
Currently, one of the most promising approaches to antiviral therapy is the development of inhibitors of the multifunctional non-structural (NS)3/NS4A heterocomplex serine protease. Validation of HCV NS3/NS4A protease as an effective target for anti-HCV therapy was recently shown by three research teams using small-molecule competitive drug inhibitors directed at the NS3 catalytic binding site. However, during monotherapy, resistant HCV isolates were selected rapidly in patients treated with NS3/4A protease inhibitors, indicating that combination therapy with other classes of anti-HCV drugs may be necessary to avoid the development of resistance. We will report the application of our high-throughput/high-content biochemical and cell-based fluorescence assays to identify and characterize in vitro and in cellulo a novel class of nanomolar noncompetitive allosteric inhibitors of the HCV NS3/4A heterocomplex serine protease. Our exciting results underscore the enormous potential of marine-based compounds as potent, naturally occurring antiviral agents targeted at viral protease-associated replication complexes. This work is funded by a Canadian Institutes of Health Research (CIHR) operating grant to Dr. F. Jean.
5:30 Grand Opening Reception in the Exhibit Hall
6:30 End of Day
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