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WEDNESDAY, APRIL 28
7:45 am Continental Breakfast Break-Out Discussions
Roundtable Topic: Kinase Targets
Moderator: Michael Soth, Ph.D., Research Scientist, Discovery Chemistry, Hoffman-La Roche Inc.
• Balancing selectivity with efficacy: how early to do toxicity studies
• Value and dangers of covalent inhibitors
• Experiences with allosteric inhibitors
Roundtable Topic: Mining the Natural Compound Library
Moderator: Allan SY Lau, M.D., Professor, Cytokine Biology Group and BioScreening Unit, Li Ka Shing Faculty of Medicine, University of Hong Kong
• Natural sources: medicinal herbs, plants, minerals,terrestrial and marine sources
• Approach : identification of biomarkers
• Application: Uses and Toxicity
Roundtable Topic: New Translational Technologies for Autoimmune and Inflammatory Drug Discovery
Moderator: Juswinder Singh, Ph.D., CSO, Avila Therapeutics
• How useful are current technologies for translational medicine in autoimmunity?
• Which targets are most useful for translational technologies?
• How useful are covalent probes to study target inhibition preclinically and clinically
8:55 Chairperson's Opening Remarks
Yousef Al-Abed, Ph.D., Professor and Director, Department of Medicinal Chemistry, Feinstein Institute
9:00 Synthesis and SAR of 2-Pyridinylbenzimidazoles as Human Histamine H4 Antagonists
Jennifer Venable, Ph.D., Senior Scientist, Immunology Chemistry, Johnson & Johnson PRD
A series of 2-phenylbenzimidazoles were evaluated as human histamine H4 receptor ligands following an initial hit from a high throughput screening campaign. While this series was promising, certain analogues demonstrated strong affinity for the hERG channel and undesirable PK properties. It was hypothesized that a reduction in overall lipophilicity may reduce these liabilities. Therefore, a series of 2-pyridylbenzimidazoles was investigated. Optimization of this series led to the discovery of a potent antagonist which demonstrated reduced affinity for the hERG channel and in-vivo efficacy in several models of inflammation. The synthesis, SAR, and corresponding functional activities of the 2-pyridylbenzimidazoles will be presented.
9:30 CPSI-2364: An Orally Efficacious Inhibitor of Proinflammatory Cytokine Production for Autoimmune and Inflammatory Diseases
Vidal de la Cruz, Ph.D., Vice President, Cytokine PharmaSciences, Inc.
CPSI-23264 is a synthetic small molecule that inhibits the over-production of proinflammatory cytokines. As an injectable, it is known to be clinically active in psoriasis, Crohn's disease and ERCP-induced pancreatitis. A recently developed oral form is highly active in animal models of diease (endotoxin challenge, diabetes, POI). A Phase I clinical study with the oral form will be completed by the end of 2009. A Phase II trial will follow shortly thereafter in 2010.
10:00 Summary of Rountable Disussions
10:15 Coffee Break, Poster and Exhibit Viewing
11:00 Modulating Inflammation with a Selective Inhibitor of the Immuno-proteasome
Christopher J. Kirk, Ph.D., Director, Preclinical Research, Onyx Pharmaceuticals
The proteasome has been validated as a drug target in oncology with the approval of bortezomib (VelcadeTM) for the treatment of multiple myeloma. Proteasome inhibitors have potent anti-inflammatory activity in preclinical models but lack a sufficient therapeutic window for use in chronic diseases such as rheumatoid arthritis (RA), inflammatory bowel disease (IBD), and systemic lupus erythematosus (SLE). Recently, we have discovered a selective inhibitor of the immunoproteasome (PR-957, now referred to as ONX 0914) and have shown that this unique form of proteasome is necessary for multiple aspects of immune responses, that selective inhibition of the immunoproteasome is efficacious in mouse models of RA, IBD, and SLE, and that the anti-inflammatory activity of ONX 0914 occurs at well tolerated doses.
11:30 What is the role of sPLA2 enzymes in disease? The discovery of sPLA2 inhibitors
Joaquim Trias, Ph.D., Senior Vice President, Preclinical Development, Anthera Pharmaceuticals
Secretory phospholipases A2 have been implicated in many inflammatory diseases. The discovery of novel inhibitors by a combination of screening and rational-drug design, and their effects in vivo led to the development of novel cardiovascular therapies.
12:00 pm End of Conference
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