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THURSDAY, APRIL 29
7:30 am Breakfast Workshop Presentation (Sponsorship Opportunity Available) or Morning Coffee
8:15 Chairperson's Opening Remarks
Michael J. Sofia, Ph.D., Vice President, Chemistry, Pharmasset, Inc.
8:20 KEYNOTE
Telaprevir: Discovery, Homologues and Clinical Update
 Youssef Bennani, Ph.D., Vice President Drug Innovation, Research Management, Vertex Pharmaceuticals
Telaprevir is a leading HCV protease inhibitor, currently in late phase 3 clinical trials. Its discovery, preclinical and clinical development represent a good example of "pushing the frontiers of medicinal research and development." The challenges in design, synthesis, and fine-tuning of Telaprevir's pharmacokinetic parameters will be presented.
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9:00 Protein Silencing of Hepatitis C Virus NS3/4A Protease in vitro and in vivo With AVL-181
Juswinder Singh, Ph.D., CSO, Avila Therapeutics
Using a novel structure-based design platform AvilomicsTM, we have discovered AVL-181, a specific irreversible inhibitor of HCV NS3/4A protease in biochemical and replicon assays. Our irreversible inhibitor has a number of important benefits over current reversible inhibitors candidates and shows excellent potency against clinically arising mutations. The inhibitor is also highly selective for host proteases because it targets a non-catalytic Cys residue only in HCV protease.Our unique mechanism of drug action durably inhibits HCV protease after a single exposure as measured in a novel in vivo model. Due to the rapid and complete protein silencing of the HCV protease by AVL-181, the functional half-life of this novel inhibitor is dependent on protein turnover rather than on continuous exposure to drug. We will present AVL-181's excellent pharmacokinetics, unique mechanism of action and its safety profile.
9:30 Recent Developments in HCV NS3/4A Protease Inhibitor
Nigel Liverton, Ph.D., Distinguished Senior Investigator, External Discovery and Preclinical Sciences, Merck Research Laboratories
Efforts toward improved HCV treatment options include the development of direct antiviral agents which inhibit key steps in viral replication, with HCV NS3/4A protease being a particularly attractive, clinically validated target. The design and discovery of MK-7009 as well as other HCV NS3/4a protease inhibitors will be presented.
10:00 Networking Coffee Break, Poster and Exhibit Viewing
10:45 Boron and Non-Boron-Based HCV NS3/4 Protease InIhibitors: Discovery of a Novel Motif Possessing High Potency against PI-Resistant Mutants
Wieslaw Kazmierski, Ph.D., Senior Chief Scientist, HCV Medicinal Chemistry, GlaxoSmithKline
We will discuss the joint effort of GlaxoSmithKline and Anacor Pharmaceuticals, Inc. to discover novel boron-based, active site-directed HCV Protease Inhibitors. Potent, proprietary inhibitors with both oxaborole and benzoxaborole (CBO)-moieties at various P1'-P4 positions were synthesized in order to explore enzyme active site aminoacid residue- boron interactions. Findings from this work led to the discovery of novel PIs with high potency against major PI-resistant mutants and the PK properties of the leading molecule supporting potential QD or BID dosing in human.
11:15 HCV-Protease Inhibitors: Current and the Next Generation
Atul Agarwal, Ph.D., Senior Director, Computational Chemistry & Informatics, Achillion Pharmaceuticals, Inc.
11:45 TMC435 Clinical Update and In Vitro Combination
Gregory Fanning, Ph.D., Senior Director, HCV Research, Tibotec BVBA
12:15 Sponsored Presentation (Opportunity Available)
12:30 Walk and Talk Luncheon in the Exhibit Hall (Last Chance for Poster and Exhibit Viewing)
1:55 Chairperson's Remarks
Flossie Wong-Staal, Ph.D., Chief Scientific Officer, iTherX Pharmaceuticals, Inc.
2:00 Discovery of Potent and Mechanistically Distinct Inhibitors of HCV Entry
William C. Olson, Ph.D., Senior Vice President, Research & Development, Progenics Pharmaceuticals, Inc.
We used a high-throughput screen based on HCV pseudo-particle (HCVpp) technology to identify multiple drug-like chemotypes that selectively blocked HCV entry. Following optimization, lead compounds demonstrated low- to sub-nanomolar potency against a panel of genotype 1 HCVpp and replication-competent HCV. Different lead series demonstrated low cytotoxicity, high selectivity, favorable ADME properties and distinct modes of blocking HCV entry. These compounds warrant further exploration for their potential to provide new classes of direct antiviral therapies for HCV.
2:30 Core Protein: A New Target for the Development of Novel Small Molecule Inhibitors of HCV
A. Donny Strosberg, Ph.D., Professor, Department of Infectology, Scripps Research Institute-Florida
We have developed assays to identify inhibitors of a non-enzymatic target: core, the HCV capsid protein. These ELISA, TR-FRET and ALPHA screen assays are based on inhibition of core dimerization. Small molecules have been identified with single digit micromolar IC50s. Some of these compounds were evaluated on HCV-infected hepatoma cells, and inhibited infectious HCV production with EC50 as low as 0.7 micromolar. These compounds constitute good molecular probes for the study of the role of core in the HCV life cycle, and may also serve as initial structures for the development of novel anti-HCV drugs.
3:00 Networking Refreshment Break
3:20 Development of SR-B1 Modulators as HCV Entry Inhibitors
Jeffrey McKelvy, M.D., Ph.D., CEO, iTherX
Scavenger Receptor B1 (SRB1) is a hepatocyte membrane protein essential for HCV entry. We have developed orally bioavailable small molecules which bind to SR-B1 with high affinity and inhibit HCV entry and infectivity. Our most advanced compound, ITX 5061, has demonstrated very good preclinical and human safety. We are initiating two proof-of-concept clinical studies: one in chronically infected HCV patients and one in HCV patients undergoing liver transplantation.
3:50 Targeting TLR7
James Appleman, M.D., Vice President Preclinical Biology and Translational Research, Anadys
4:20Mechanism of HCV Resistance to Cyclophilin Inhibitors
Hengli Tang, Ph.D., Assistant Professor, Biological Science, Florida State University
Cyclophilin inhibitors have emerged as candidates as a novel class of anti-HCV drug as HCV replication exhibits a strong dependence on Cyclophilin A. We have characterized mutations in HCV genome that confer resistance to Cyclophilin inhibitors and render Cyclophilin independent infection in vitro. Here we will discuss the potential mechanism of this resistance.
450 End of Conference
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