|
Friday, March 28
8:30am Chairperson's Remarks
Christopher Burns, Ph.D., Vice President, Research, Protez Pharmaceuticals 8:35 Discovery and Advancement of 4�ESubstituted Nucleosides for the Treatment of Hepatitis C
David B. Smith, Ph.D., Principal Research Scientist, Medicinal Chemistry, Roche Palo Alto LLC
Hepatitis C virus (HCV) was first characterized in 1989 as the major cause of non-A/non-B hepatitis infections. An estimated 3% of the global human population is infected by this life threat-ening virus, an infection that often leads to cirrhosis, hepatocellular carcinoma, and liver failure in later life. Among key enzymes, the HCV genome encodes an RNA-dependent RNA poly-merase (NS5B), which is responsible for the synthesis of new viral RNA strands. Based on teachings from related nucleoside work, and following a systematic approach, we discovered that certain 4�Esubstituted nucleosides are potent inhibitors of the NS5B polymerase. As a result of these studies, 4�Eazidocytidine (R1479) entered clinical trials and was later replaced by its pro-drug R1626. An overview of our efforts in this area, including an update on the ongoing clinical progression of R1626 in the treatment of HCV infected patients, will be presented. 
9:05 Beyond Boceprevir: Development of Second Generation HCV NS3 Protease Inhibitor
Kevin Chen, Ph.D., Senior Principal Scientist, Anti-Infectives & Tumor Biology, Schering Plough Research Institute
In the search for the next generation of HCV NS3 protease inhibitor drug candidate, our major effort has been focused on the development of novel P3 capping groups. The discovery of several potent capping series led to the inhibitors that are 10 x more potent than Boceprevir, extremely selective and with favorable pharmacokinetic properties. The SAR development and PK profile of these new classes of inhibitors will be discussed. 9:35 Allosteric Non-Nucleoside Inhibitors of HCV RNA Polymerase (NS5B)
Christopher Burns, Ph.D., Vice President, Research, Protez Pharmaceuticals
The current treatment for Hepatitis C virus infection typically involves a combination of ribavirin and interferon. This regimen suffers from side effect, efficacy, and patient compliance issues. It is forseeable that future treatment modalities could more mirror the options available for HIV infection, which center on combination therapy of nucleoside and non-nucleoside nucleic acid polymerase inhibitors (the NRTIs and NNRTIs) and viral protease inhibitors. In the corresponding case of HCV, significant advances have been achieved along all three fronts. This presenta-tion will focus on recent advances in the quest for potent and selective non-nucleoside small molecule HCV RNA polymerase inhibitors. Highlights and key insights on the discovery and
progression of two different clinical candidate chemical series (pyranoindoles and benzofurans) discovered at ViroPharma/Wyeth will be presented. 10:05 Technology Spotlight
(Sponsorship Available) 10:20 Coffee Break in the Foyer
11:00 Agonists of GPR119 / GDIR Mediate Glycemic Control via Glucose Dependent Insulin and Incretin Release
Robert M. Jones, Ph.D., Director, Medicinal Chemistry, Arena Pharmaceuticals
Pancreatic β-cell dysfunction is a hallmark event in the pathogenesis of type 2 diabetes. Injectable peptide agonists of the GLP-1 receptor have shown significant promise as anti-diabetic agents by virtue of their ability to amplify glucose-dependent insulin release and preserve pancreatic
β-cell mass. These effects are mediated via stimulation of cyclic AMP through
β-cell GLP-1 receptors. Here we report that the Gαs-coupled receptor GPR119 is largely restricted to insulin-producing
β-cells of pancreatic islets together with L-cells of the GI tract. Based on the func-tional properties of GPR119 described herein, we propose terming this receptor GDIR (孄lucose-dependent insulinotropic receptor�E. Unlike receptors for GLP-1 and other peptides that medi-ate enhanced glucose-dependent insulin release, GPR119 has proven amenable to the development of potent, orally active, small-molecule agonists. Specific orally active GPR119/GDIR agonists may offer significant promise as novel anti-diabetics acting in a glucose-dependent fashion. 11:30 The Discovery of Novel CB1 Receptor Antagonists
Phill Cowley, Ph.D., Section Head, Chemistry, Organon Research
The field of cannabinoid research has continued to attract substantial interest since cloning of the CB1 and CB2 receptors and the identification of the endogenous ligands (endocannabinoids) for these receptors in the 1990s. Cannabinoid receptor agonists, antagonists and compounds designed to modulate endocannabinoid levels (for example through inhibition of the degrada-tion enzyme, FAAH) all continue to show therapeutic potential in a number of disease states. This presentation will focus on the identification of CB1 receptor antagonists. These compounds are expected to have a number of possible therapeutic applications, particularly in the treatment of obesity. The identification of hits from a screening campaign utilising a binding assay and their subsequent optimisation to improve potency and selectivity will be described. Further refinement of the pharmacokinetic profile of these compounds will also be discussed, leading to compound (1). In addition, the presentation will describe how an alternative screening campaign, in a functional assay of CB1 receptor antagonism, led to the identification of a series of allosteric antagonists of the CB1 receptor. 
12:00pm Luncheon Workshop
(Sponsorship Available) or Lunch on Your Own 1:00 Chairperson's Remarks
Aubrey Mendonca, President ChemRoutes Corporation 1:05 Discovery of Novel DPP-4 Inhibitors
Tesfaye Biftu, Ph.D., Medicinal Chemistry, Distinguished Senior Investigator, Merck & Co., Inc.
Replacement of the triazolopiperazine group of sitagliptin with a diazepanone moiety gave 1, which was selected as a backup preclinical candidate. Using molecular modeling based on x-ray crystallography of DPP-4 bound to these inhibitors, we envisioned that a cyclohexylamine group could be an appropriate replacement for the central β-amino butanoyl portions of sitaglip-tin and 1, providing a ring constrained analog such as 2. In this presentation, we will summarize the discovery of sitagliptin and the diazepanone 1 and discuss the rational design and synthesis of the novel, potent, selective and orally bioavailable cyclohexylamine 2. 
1:35 Discovery of Taranabant, a Novel CB1R Inverse Agonist for the Treatment of Obesity
Ping Liu, Ph.D. Research Fellow, Department of Medicinal Chemistry, Merck Research Laboratories
Taranabant is a structurally distinct and highly efficacious CB1 receptor inverse agonist, which is undergoing clinical evaluations for the treatment of obesity. In this presentation, the discovery effort that led to the identification of taranabant will be detailed, including strategies to optimize potency / in vivo efficacy and approaches to minimize bioactivation / formation of reactive metabolites. Although the scaffold of taranabant is acyclic in nature, it is structurally rigid as supported by solution and solid state conformation studies. These results along with pharmaco-phore mapping will also be discussed. 
2:05 Fused Pyrimidine Heterocycles as Selective 5-HT2A Antagonists
Brock T. Shireman, Ph.D., Senior Scientist, Neuroscience Drug Discovery, Johnson & Johnson Pharmaceutical Research and Development, L.L.C.
The synthesis, SAR, and preliminary in vivo data for a novel series of 2-alkyl-4-aryl-tetrahydro-pyrido-pyrimidines and 2-alkyl-4-aryl-tetrahydro-pyrimido-azepines will be described. Representa-tive compounds were shown to be subtype selective 5-HT2A antagonists. Optimization of ring size (m and n) and substituents (R1, R2 and R3) were found to have a profound effect on affinity, selectivity and in vivo efficacy. 
2:35 Medicinal Chemistry Efforts Leading to the Optimization of Histamine H3 Receptor Antagonists
Robert J. Altenbach, Research Investigator Chemist, Neuroscience Research, Global Pharmaceutical Research and Development, Abbott Laboratories
Blockade of the hERG channel by pharmaceuticals has been implicated in the prolongation of the QT interval in the rhythm of the heart and can lead to fatal arrhythmias. Screening for the affinity of compounds at the hERG channel has become routine in the pharmaceutical industry and designing high selectivity against this channel is a critical task for the medicinal chemist. In our histamine-3 receptor (H3R) antagonist program, some early compounds were found to have an unsatisfactory selectivity for potency at the H3R over hERG. This presentation will describe how we decreased affinity for the hERG channel in different series while maintaining excellent drug-likeness, retaining good in vitro potency and behavioral activity. In addition, some design strategies that reduced the phospholipidosis potential of some early compounds will be discussed. 3:05 Close of Conference
|
Japanese
Korean
English