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SUNDAY, MAY 11

4:00-6:00pm Conference Pre-Registration 

MONDAY, MAY 12

7:30am – 6:00pm Registration Open

7:30am Morning Coffee

8:30 Chairperson’s Remarks

8:40 New Targets for Chronic Pain Therapy: Challenges and Opportunities 
Catherine Abbadie, Ph.D., Senior Research Fellow, Department of Pharmacology, Merck & Co., Inc. 
Pain is a major unmet medical need but drug discovery remains challenging. There is a need for new therapies that provide more predictable efficacy in all patients with improved tolerability. Over the last decade, understanding the basic mechanisms contributing to the generation of neuropathic or inflammatory pain in pre-clinical animal models has greatly improved. The complexity of pain processing in clinical pain conditions and in animal models has revealed many time-related changes and an abundance of molecular drug targets. There continues to be insecurity, however, about new target validation in clinical pain and thus most analgesia development is of high risk for evolving new pain therapies. This presentation will review the rationale behind a number of these mechanism-based approaches and discusses specific challenges that they face. 

9:25 Novel and Emerging Techniques in Pain Management
Eugene Viscusi, M.D., Director of Regional Anesthesia and Acute Pain Management, Department of Anesthesiology, Thomas Jefferson University
Current pain management needs remain unmet. In spite of the tremendous emphasis on patients’ rights to pain control and position statements and guideline by societies and accrediting bodies, large numbers of patients suffer unrelieved pain. Older drugs and technologies fall short or satisfying the needs. Novel and emerging technologies must focus on ease-of-care, reduced abuse liability, improved side effects and reduction in analgesic “gaps.”

10:10 Networking Coffee Break

10:40 Targeting TRPV1 Receptor Antagonist for the Treatment of Pain 
Chih-Hung (Lance) Lee, Ph.D., Senior Group Leader, Abbott Neuroscience
The vanilloid receptor TRPV1 is a membrane-bound, non-selective cation channel that can be activated by a number of noxious stimuli, including heat, protons, and ligand agonists such as capsaicin. TRPV1 antagonists have been discovered that show potent, competitive inhibition of capsaicin-induced Ca2+ influx in vitro and potent antinociception in vivo. High-throughput screening of the Abbott compound library identified several hits. Lead optimization of these hits yielded compounds with improved pharmacokinetic and pharmaceutical properties. The discovery and characterization of lead compounds for clinical evaluation as potential novel agents for pain management will be discussed.

11:10 Design & Synthesis of TRPV1 Antagonists
Gurdip Bhalay, Ph.D., Head, Chemistry Project Team, Novartis Institutes of BioMedical Research
Vanilloid receptor 1 (VR1, TRPV1) is a cation-selective ion channel that is expressed on primary afferent neurons and is upregulated following inflammation and nerve damage. Blockers of this channel may have utility in the treatment of chronic nociceptive and neuropathic pain. Structure morphing of a previous generation proprietary TRPV1 antagonist provided a new chemical class suitable for lead optimization. Our experience from hit-to-lead through lead optimization will be described.

11:40 Can We Identify Transient Receptor Potential Vanilloid 1 (TRPV1) Antagonists That Do Not Cause Hyperthermia?
Nuria Tamayo, Ph.D., Principal Scientist, Amgen, Inc.
The transient receptor potential vanilloid 1 (TRPV1) is a nonselective cation channel primarily expressed by a subset of nociceptive neurons in the dorsal root and trigeminal ganglia. TRPV1 can be activated by a variety of noxious stimuli, including capsaicin, extracellular acidity and heat. This activation leads to the influx of ions into the cell causing cell depolarization and leading to the sensation of pain. Antagonism of this channel could be an attractive approach for the treatment of chronic pain and inflammatory hyperalgesia.
We have recently advanced a TRPV1 antagonist AMG 517, into clinical trials as a new therapy for the treatment of pain. However, in addition to the desired analgesic effects, AMG 517 significantly increased body core temperature following oral administration. Here we will discuss our two approaches to eliminate or minimize the on-target hyperthermic effect observed with this and other TRPV1 antagonists: a) peripheral restriction and b) differential in vitro profiles.

1:10 Session Break

1:40 Chairperson’s Remarks 

1:45 Identification and Exploration of a Novel Series of Heterocyclic Cannabinoid Receptor Agonists for the Treatment of Pain
Paul D. Ratcliffe, Ph.D., Team Leader, Department of Medicinal Chemistry, Organon Laboratories Ltd., a part of Schering-Plough Corporation
CB1 receptor agonists have been suggested as possible treatments for a wide range of medical disorders including pain, spasticity, inflammation, glaucoma, nausea and emesis, neurodegenerative disorders, anxiety and hypertension. The high lipophilicity and poor water solubility of known CB1 receptor agonists have hampered their evaluation as therapeutic agents. A novel CB1 receptor agonist lead series was identified from a high-throughput screening approach. The initial screen resulted in a novel confirmed hit with poor water solubility. Hit and Lead optimization led to the identification of a series of water soluble indole-e-carboxamides. These compounds demonstrated effective levels of analgesia within a range of in vivo models. The indole-3-carboxamides were rapidly metabolized in the presence of human liver microsomes and in an endeavour to identify longer acting compounds, a number of approaches were undertaken. The strategies employed will be described, including the identification of an exciting new series of heterocyclic CB1 receptor agonists.

2:15 Potent and Orally Bioavailable Bradykinin B1 Receptor Antagonists for the Treatment of Pain and Inflammation
Chester Chenguang Yuan, Ph.D., Senior Scientist, Amgen Inc.
The bradykinin receptors (subtypes B1 and B2) are two G-protein-coupled receptors with small peptides, kinins, as their natural ligands. The B1 receptor is quickly upregulated under several inflammatory stimuli and activated by the binding of its ligands and is responsible for maintaining chronic inflammation and pain states. Blocking this receptor has been shown to reverse and/or ameliorate pain and inflammation in animal models. In this presentation, we will discuss our results in discovery, synthesis and evaluation of a series of potent, selective and orally bioavailable sulfonamide-based small molecule (read mol.) antagonists for the B1 receptor. 

2:45 Technology Watch (Sponsorship Available)

3:00 Grand Opening Refreshment Break in the Exhibit Hall 

3:40 Purinergic Receptor Antagonists: Novel Treatments for Inflammatory and Neuropathic Pain
David S. Carter, Ph.D., Research Scientist, Roche Palo Alto 
Purinergic receptors are a family of ligand gated ion channels whose endogenous ligand is ATP. Homomeric P2X3 and heteromeric P2X2/3 receptors are selectively localized at the peripheral and central terminals of non-myelinated afferent nerve fibers and, along with ATP, have been implicated in the transmission of sensory signals. Blockade of these signals with antagonists offers the potential to treat a broad range of pain conditions. This presentation will describe the lead discovery, optimization and SAR of selective drug-like antagonists; in vivo efficacy in a number of pre-clinical models outlining the therapeutic potential.

4:10 SAR Development of a Novel 6-Azauracil-Based Series of P2X7 Receptor Antagonists: Subtle Modifications to an HTS Hit to Address Potency as well as Physicochemical and Pharmacokinetic Properties
Allan Duplantier, Ph.D., Associate Research Fellow, Pfizer Global Research and Development
Parallel synthesis efforts around the amide side chain of a rule of five compliant HTS hit provided a lead compound with modest human P2X7 receptor potency (YoPro and IL-1b IC50 = 300 nM), high selectivity against a panel of receptors and channels, low rat Cl, moderate bioavailablity, but high human plasma protein binding and a low Vdss. The focus of this presentation will be on the subsequent medicinal chemistry efforts that led to potent P2X7 antagonists (IC50 < 100 nM) with good PK properties that retain their potency in the presence of human blood and that are potent in an in vivo model in which ATP-induced IL-1 production by implanted human cells is measured in the peritoneum of a mouse.

4:40 Ouch! The Painful Effects of ATP are Mediated by Activation of Specific P2 Receptor Subtypes
Diana L. Donnelly-Roberts, Ph.D., Research Investigator, Abbott Neuroscience 
ATP acting at multiple purinergic (P2) receptors, either directly on neurons (e.g. P2X3, P2X2/3 and P2Y) or indirectly through neural-gial cell interactions (P2X4 and P2X7), alters nociceptive sensitivity. This talk will highlight the emergence of selective antagonists for these P2 receptors, with emphasis on P2X7. The recent emergence of P2X7 antagonists with pre-clinical efficacy has helped to further clarify P2X7 receptor pharmacology and downstream signaling, but more importantly supports the role of P2X7 in nociception of chronic pain states. 

5:10 Happy Hour in the Exhibit Hall 

6:10 End of Day

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