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TUESDAY, MAY 13

7:30am Continental Breakfast Breakout Discussions
Topic: Non Steroidal Anti-Inflammatory Drugs (NSAIDS): 
Their Current and Future Roles in Managing Chronic Pain
Moderator: Bevyn Jarrott, Professor, Florey Neuroscience Institutes, University of Melbourne

Topic: Mixed Uptake Inhibitors and Their Therapeutic Potentials in Treating Neuropathic Pain
Moderator: Zhengming (Jimmy) Chen, Ph.D., Senior Director, Chemistry & CMC, DOV Pharmaceuticals, Inc. 

8:30 Chairperson’s Remarks

8:40 Potassium and Sodium Channel Modulators Designed to Target Neuropathic Pain
Robert Atkinson, Ph.D., Senior Research Investigator, Medicinal Chemistry, Icagen, Inc.
Ion channels play an important role in the detection, transmission and cognitive recognition of pain signals. The underlying mechanism through which ion channels are involved in the sensation of pain is through the modulation of the level of excitability of specialized nerve cells in the pain pathway. We have identified several ion channel targets including sodium channels and potassium channels that are expressed in pain pathways in both the central and peripheral nervous systems. In both our sodium and potassium channel pain programs, Icagen has identified selective compounds that demonstrate efficacy in animal models for neuropathic and inflammatory pain. These programs and an overview of the compounds that modulate the respective channels will be discussed.

9:10 Bradykinin B1 Receptor Antagonists as Novel Analgesics
Scott Kuduk, Ph.D., Senior Research Fellow, Merck Research Laboratories
The quest for improved treatments of chronic pain and inflammation continues to be an area of intense research. Human bradykinin B1 receptor antagonists embody a novel approach for the treatment of these disease states. The inducible BK B1 receptor is expressed at high levels in injured tissue and is also present in the central nervous system implying the potential for a central mode of action. A series of antagonists has been optimized to possess sub-nanomolar affinity for the human B1 receptor, acceptable pharmacokinetic properties, good CNS levels and receptor occupancy. The optimization was achieved by circumventing a number of problematic metabolic pathways, leading to compounds with properties suitable for further evaluation as potential clinical candidates.

9:40 Neuronal Nicotinic Receptor Agonists for the Treatment of Pain: The Role of Receptor Subtype Selectivity in Improving Therapeutic Index
Michael D. Meyer, Ph.D., Senior Project Leader, Neuroscience Research, Abbott Laboratories
Neuronal nicotinic receptor (NNR) agonists exhibit broad-spectrum analgesic efficacy across animal models of acute, inflammatory, and neuropathic pain. Using a first generation NNR agonist (ABT-594), analgesic efficacy in humans has now been demonstrated. However, ABT-594 exhibited a narrow therapeutic index with respect to the typical NNR side effects of nausea, emesis and dizziness. We and others have hypothesized that the analgesic and adverse effects of NNR agonists are governed through activation of distinct NNR subtypes, and through identification of subtype-selective ligands, analgesic efficacy could be retained with an improved side effect profile. Molecules exhibiting enhanced selectivity for the 42 subtype over the 3-containing ganglionic NNR subtypes have now been identified and have demonstrated improved separation between analgesic efficacy and undesired GI-related side effects in animal models. By drawing on the clinical experience with ABT-594, and using that information to develop quantitatively predictive pre-clinical models, a second generation NNR agonist has now been identified with a significantly improved tolerability profile, and is currently undergoing clinical development.

10:10 Networking Coffee Break in the Exhibit Hall

10:50 Development of Peripheral Kappa Opioid Analgesics: Targeting Pain and Inflammation at its Source
Rob Spencer, Ph.D., Director, Pre-clinical Development, Cara Therapeutics, Inc.
Opiate analgesics can act through three different types of opioid receptors, mu, delta, and kappa. Morphine, the most widely used opiate analgesic, acts primarily via activation of the mu opioid receptor located in the central nervous system (CNS). This activity in the CNS produces pain relief but is also associated with a wide array of CNS-mediated side effects including sedation, respiratory depression, and abuse liability. As a means to avoid these undesirable CNS effects while maintaining the analgesic efficacy associated with opioids, we have developed a series of peripherally-restricted kappa opioid receptor agonists that target these receptors in sensory neurons, immune cells and other peripheral tissues. These molecules have efficacy across a broad range of pain models without the adverse effects associated with mu opioids, and are currently in clinical development for the treatment of acute and chronic pain. 

11:20 Design and Pharmacological Properties of a Novel Series of Dithiolethione Compounds as Non-Steroidal Anti-Inflammatory Drugs with Minimal Gastrointestinal Toxicity
Bevyn Jarrott, Professor, Florey Neuroscience Institutes, University of Melbourne
Hydrogen sulfide is now established as an endogenous molecule that inhibits the early steps of inflammation by both reducing the expression of several pro-inflammatory cytokines and suppressing the adherence of neutrophils to the vascular mesenteric endothelium and their subsequent migration into underlying tissue. We have found that a series of 18 substituted phenyl-dithiolethiones are potent cyclooxygenase (COX) inhibitors as well as a source of hydrogen sulphide when administered in vivo. We have established the structure-activity features that exhibit variable degrees of COX-1/COX-2 selectivity with some being non-selective and others being as potent and as selective as the COX-2 inhibitor, rofecoxib. These compounds are anti-inflammatory in peripheral models of pain and inflammation but are without overt gastrointestinal toxicity. They may be neuroprotective in diseases such as Alzheimer’s disease and multiple sclerosis, which have prominent central inflammatory pathologies. 

11:50 Targeting Selective FAAH Inhibitors for the Treatment of Inflammatory Pain
Douglas S. Johnson, Ph.D., Senior Principal Scientist, Pfizer Research and Development
Fatty acid amide hydrolase (FAAH) is an integral membrane enzyme that degrades the fatty acid amide family of signaling lipids, including the endocannabinoid anandamide. Genetic or pharmacological inactivation of FAAH leads to analgesic and anti-inflammatory phenotypes in rodents without showing the undesirable side effects observed with direct cannabinoid receptor agonists, indicating that FAAH may represent an attractive therapeutic target for the treatment of inflammatory pain. This talk will describe a series of piperidine/piperazine ureas, which inhibit FAAH in a time-dependent manner by covalently modifying the enzyme’s active site serine nucleophile. Activity-based proteomic profiling revealed that these urea FAAH inhibitors were completely selective for FAAH relative to other mammalian serine hydrolases.

12:20pm Close of Targeting Pain with Novel Therapeutics Conference