8:30am Chairperson’s Remarks
Jeff Zablocki, Ph.D., Head of Chemistry, CV Therapeutics

 RECENT FDA APPROVAL 

8:35       A Medchem Case Study on the Discovery of Regadenoson (Lexiscan), a Pharmacological Stress Agent  that is an Agonist for the A2A Adenosine Receptor
Jeff Zablocki, Ph.D., Head of Chemistry, CV Therapeutics
Regadenoson is the first non-adenosine agonist to be approved by the United States Food and Drug Administration (US FDA) as a pharmacological stress agent indicated for radionuclide myocardial perfusion imaging (MPI). The discovery of Regadenoson started in 1999 with a group scientists that hypothesized that a selective A2A adenosine receptor (AdoR) agonist may have fewer side effects than the MPI agent, adenosine Adenoscan™.    Our medicinal chemistry efforts were directed towards discovering a novel functionally selective A2A AdoR agonist with a short pharmacodynamic half life designed by the incorporation of 2-pi-substituted adenosine derivatives- 2-(2-thienyl), 2-(N-1-pyrazolyl), 2-(4-pyrazolyl), and 2-(propargylphenylethyl) adenosine derivatives. 

 ALZHEIMER THERAPEUTICS

9:05       Screening for Alzheimer Therapeutics
Varghese John, Ph.D., Director Alzheimer’s Drug Discovery Network, The Buck Institute for Age Research
This C-terminal cleavage of APP (amyloid precursor protein) gives rise to a neuronal cell-killing molecule called C31 (derived from the 31 amino acids from the carboxyterminal tail of APP), which was discovered by our laboratory at the Buck Institute. Using a transgenic mouse that modeled Alzheimer’s disease, we found that we can prevent the C-terminal proteolysis in vivo by mutating APP695 (Asp664􀃆Ala), and this point mutation in APP results in Tg mice lacking the AD phenotype. Identification of inhibitors of this C-terminal cleavage represent a novel therapeutic approach for AD.

9:35       Discovery, SAR and Antiparkinsonaim Effect of Novel Positive Allosteric Modulators (PAMs) and Ago-potentiators of Metabotropic Glutamate Receptor Subtype 4 (mGluR4)
Craig W. Lindsley, Ph.D., Associate Professor of Pharmacology, Associate Professor of Chemistry, Vanderbilt UniversityCorey R. Hopkins, Ph.D., Associate Director, Medicinal Chemistry, Vanderbilt University Medical Center
This talk will concern the discovery and development of three novel series of mGluR4 PAMs and ago-poentiators, VU0155041, VU0080241 and VU001171, which are more potent, efficacious and possess improved properties relative to (-)-PHCCC.  Moreover, VU0155041 displayed significant efficacy ion preclinical Parkinsonian models, further validating the therapeutic role of mGLuR4 activation in PD.

10:20     Coffee Break

 PAIN INHIBITORS

11:00     Inhibitors of Fatty Acid Amide Hydrolase (FAAH): SAR and Results in Pre-clinical Pain Models
J. Guy Breitenbucher, Ph.D., Research Fellow, Team Leader, Pain and Related Disorders Johnson & Johnson, PRD San Diego
 Pharmacologically active preparations of Cannabis sativa have been recognized since ancient times as having potentially useful therapeutic effects, including analgesia.  With the discovery and cloning of the cannabinoid receptors CB1 and CB2, and the subsequent discovery of anandamide, the first endogenous substance with agonist activity at both receptors, a rationale for the analgesic effects of cannabis was developed. Anandamide has a short half-life, due to rapid hydrolysis by the enzyme fatty acid amide hydrolase (FAAH) resulting in low resting concentrations in the CNS. Inhibition of this enzyme would be expected to prolong the duration of action of endogenously released anandamide.  Indeed, FAAH knockout mice have been described and have elevated resting brain concentrations of anandamide, and manifest a phenotypic analgesia in several commonly used models of pain. Furthermore, known inhibitors of FAAH show amelioration of pain behaviours in rats. The present account describes the discovery of a novel classes of FAAH inhibitors and describes our work to characterize the SAR and pharmacological actions of these FAAH inhibitors.

11:30     Design & Synthesis of TRPV1 Antagonists with Improved Physicochemical and Pharmacokinetic Properties
Hui-Ling Wang, Ph.D., Senior Scientist, Department of Medicinal Chemistry, Amgen Inc.
Over the past several years TRPV1 has emerged as an exciting target for the treatment of chronic pain.  After the identification of our first TRPV1 clinical candidate AMG 517, continuing optimization of in vitro potency, physicochemical, and pharmacokinetic properties led to the discovery of AMG 628, a second-generation candidate with excellent aqueous solubility.

12:00pm          Luncheon Presentation or Lunch on your own(Opportunity Available)

 ANTIVIRAL AND ANTINFECTIVE THERAPEUTICS – SPECIAL FOCUS, HCV AND HIV INHIBITORS

1:00       Chairperson’s Remarks
Aubrey Mendonca, President, & CEO, ChemRoutes Corp.

1:05       Designing Oral gp120 Inhibitors for the Treatment of HIV
Don Middleton, Ph.D., Senior Director, Department of Discovery Chemistry, Pfizer Global Research and Development

1:35       Discovery of HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitors That Maintain Excellent Potency Against NNRTI-Resistant Mutant Viruses
Zachary Sweeney, Ph.D., Principal Research Scientist, Medicinal Chemistry, Roche Pharmaceuticals
This presentation will describe our structure based design program targeting next-generation NNRTIs for the treatment of HIV infection.  Starting from a HTS hit, rational modification resulted in the identification of a number of candidate compounds that have superior potency against wild-type and resistant viruses as well as excellent pharmacokinetics in animal species.  Example compounds were well tolerated in GLP toxicity studies.  Over 120 co crystal structures of inhibitors bound to HIV-RT were obtained in the course of this work, and fragment screening and deconstruction exercises, as well as surface plasmon resonance experiments that provide insight to the binding of these NNRTIs will be described.

2:05       Discovery and Preclinical Evaluation of Tri-cyclic HIV-1 Integrase Inhibitors
Choung U. Kim, Ph.D., Vice President, Chemistry, Gilead Sciences
A number of highly potent Tri-cyclic HIV integrase inhibitors have been identified via rational drug design. SAR and pharmacokinetic studies of these inhibitors will be discussed.

2:35       Discovery and Early Clinical Development of TD-1792, a Unique, Heterodimer Antibiotic
Dan Marquess, D. Phil., Vice President, Medicinal Chemistry, Theravance
This presentation will describe Theravance multivalent approach to heterodimer antibiotics. The medicinal chemistry and SAR of in vitro microbiology of heterodimer compounds will be described. How this in vitro activity relates to activity in vivo efficacy data in pharmacological models of bacterial infection and PK/PD relationships will also be discussed. Preliminary clinical data will also be presented. TD-1792 demonstrated marked bactericidal activity in vitro and was 30 fold more potent than vancomycin against methicillin-resistant Staphylococcus aureus (MRSA).

3:05       Close of Conference

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