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December Meeting
The 936th Meeting of the Northeastern Section of the American Chemical Society

Northeastern Section
American Chemical Society (NESACS)

Symposium Innovative Treatments for Unmet Medical Needs

Organized by the Medicinal Chemistry Section of the Northeastern Section, American Chemical Society Sponsored By

Thursday December 12th, 2013 Genzyme, a Sanofi Company

153 Second Avenue, Waltham Massachusetts 02451
Northeastern Conference Room

3.00 pm 3.15 pm

Refreshments Welcome Raj (SB) Rajur, NESACS Medicinal Chemistry Program Chair, CreaGen Biosciences, Inc., Woburn, MA Introductory Remarks (Moderator) Norton P. Peet, Director of Chemistry, Microbiotix, Inc., Worcester, MA Eugene Piatnitski Chekler Worldwide Medicinal Chemistry, Pfizer Inc. Title: Tissue Selective Androgen Receptor Modulators (SARMs): A Path to a Clinical Candidate John Williams Microbiotix, Inc., Worcester, MA Title: Novel Inhibitors of the Pseudomonas Type Three Secretion System Barry Toure Novartis Institute for Biomedical Research, Boston, MA 02451 Title: Identification of NVP-TNKS656: a Highly Potent, Selective, and Orally Active Tankyrase Inhibitor Social Hour Dinner

3.20 pm

3.30 pm 4.15 pm

4.15 pm 5.00 pm

5.00 pm 5.45 pm

6:00 pm 6.45 pm 6:45 pm 7.45 pm

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7:45 pm 8.30 pm

Keynote Presentation Introduction: David Aldous, Head of Boston LGCR, Sanofi, Waltham MA Zhongli Gao Genzyme-Sanofi, Waltham, MA Title: A Winding Journey of Medicinal Chemistry Toward the Discovery of a Potent, Selective, and Orally Bioavailable Histamine H3 Receptor Antagonist for Cognitive Impairment: From a Biological Concept to a Development Candidate

YOU MUST REGISTER IN ADVANCE BUT THERE IS NO REGISTRATION FEE TO ATTEND THE SYMPOSIUM; DINNER RESERVATIONS ARE REQUIRED. PUBLIC IS INVITED
Dinner reservations should be made no later than noon, Thursday, December 5 , 2013. Reservations are to be made using PayPal: http://acssymposium.com/paypal.html. Select pay with credit or debit card option and follow the additional instructions on the page. Members, $30; Non-members, $35; Retirees, $20; Students, $10. Reservations for new members and for additional information, contact the secretary, Anna Singer, at (781) 272-1966 between 9am and 9pm or e-mail at secretary@nesacs.org. Reservations not cancelled at least 24 hours in advance must be paid. Directions to Genzyme, a Sanofi Company Waltham Site
th

From North or South 95/Rt 128 South. Take Exit 27B/Winter Street. Follow signs for Second Avenue (stay in right lane) Take a right after the Embassy Suites Hotel onto Second Avenue. Go past Costco on the right At ADP take a right between ADP garage and ADP offices (There is a sign directing you to Genzyme) Proceed about 100 feet Genzyme will be on the right Link to directions: http://www.genzyme.com/~/media/Files/GenzymeCorp/PDF/directions_waltham.pdf

Speakers Bio and Abstracts:

Eugene Piatnitski Chekler, Ph. D. Senior Principal Scientist Worldwide Medicinal Chemistry, Pfizer Inc. Title: Tissue Selective Androgen Receptor Modulators (SARMs): A Path to a Clinical Candidate

Abstract: As a potential treatment for muscle frailty, the SARM project team has identified a tissue-selective SARM compound with excellent properties. The lead series was developed using structure-based drug design with several inhouse and external crystal structures of androgen receptor binders in conjunction with medicinal chemistry design with the aim to reduce lipophilicity. The lead compound is representative of a series of cyanoisoquinolines which show good potency and efficacy in an androgen receptor predictive anabolic assay, excellent selectivity in an assay predictive of androgenic activity, excellent HT-ADME properties and good/excellent oral bioavailability in three preclinical species. In addition, data from disease models and safety studies will be shared in this presentation. Biographical sketch: Eugene Chekler joined the Medicinal Chemistry department at Pfizer after a merger with Wyeth. Throughout his career, he worked on a wide range of projects in the fields of muscular-skeletal therapy, oncology, epigenetics, cardiovascular diseases, endocrinology, and protein misfolding. He directly contributed to two molecules that

PLEASE POST progressed to clinical studies in the areas of cardiovascular and muscular-skeletal disorders. Prior to joining Wyeth in 2005, Eugene Chekler spent four years ImClone Systems, an oncology focused biotechnology company, where he was a team leader. Eugene Cheklers current research interests are focused on muscle therapies for a variety of diseases. . John Williams, Ph.D. Senior Scientist Microbiotix, Inc., Worcester, MA Title: Novel Inhibitors of the Pseudomonas Type Three Secretion System Abstract: The type three secretion system (T3SS) is a bacterial virulence factor found in many gram negative pathogens that acts as a molecular machine, capable of introducing toxins directly into host cells. Although not essential for survival, the presence of a functional T3SS is highly correlated with poor clinical outcomes in Pseudomonas infections, particularly in cystic fibrosis patients. Through an internal HTS campaign, we have identified a novel set of highly selective inhibitors, based on a phenoxyacetamide core, that inhibits the proper functioning of this multi-protein system. We have thus far optimized the structure of the phenoxyacetamide to provide inhibitors with low M activity in a T3SS toxin/-lactamase fusion protein secretion assay. Development of a comprehensive set of SARs in the phenoxyacetamide series will be presented.

Biographical Sketch: Dr. Williams attended the University of Wisconsin-Parkside where he earned a B.S. in Biology and Chemistry. He entered the Medicinal Chemistry program at the University of Michigan where he studied nucleoside antivirals under the instruction of Dr. Leroy Townsend and Dr. John Drach. Upon completing his Ph.D. in 2003, he joined the group of F. Ivy Carroll at the Research Triangle Institute (RTI), where he contributed to a program studying drugs of abuse. In 2005, he joined Microbiotix, Inc. in Worcester, MA where he continues to work on antibacterial, antiviral, and biodefense projects.

Barry Toure, Ph.D. Investigator III Novartis Institute for Biomedical Research, Boston, MA Title: Identification of NVP-TNKS656: a Highly Potent, Selective, and Orally Active Tankyrase Inhibitor Abstract: Tankyrase 1 and 2 have been shown to be druggable nodes in the Wnt pathway. As such, there has been intense interest in developing agents suitable for modulating the Wnt pathway in vivo by targeting this enzyme pair. By utilizing a structure-based design, the core of XAV939 was optimized into a more stable, more efficient, but less potent dihydropyran motif. This core was combined with elements of other screening hits to yield highly potent, selective tankyrase inhibitors that are novel three pocket binders. NVP-TNKS656 was identified as an orally active antagonist of Wnt pathway activity in the MMTV-Wnt1 mouse xenograft model. With an enthalpy-driven thermodynamic signature of binding, highly favorable physicochemical properties, and high lipophilic efficiency, NVP-TNKS656 is a novel tankyrase inhibitor that is well suited for further in vivo validation studies.

Biographical Sketch: Barry Toure joined the Oncology Department of the Novartis Institutes for Biomedical Research Inc. in Cambridge, MA in 2006 after a short postdoc stay at Columbia University. Since then, he has worked on a broad

PLEASE POST range of therapeutic targets including protein-protein interactions, kinases, PARylation enzymes, transcription factors and cancer metabolism targets. He has led and continue to lead a number of the projects. He also maintains an active research interest in the development of new synthetic technologies to facilitate the drug discovery cycle such as the development of practical C-H oxidation reactions to assess and identify drug metabolites.

Zhongli Gao, Ph.D. Lead Research Investigator II Genzyme-Sanofi, Waltham, MA Title: A Winding Journey of Medicinal Chemistry Toward the Discovery of a Potent, Selective, and Orally Bioavailable

Histamine H3 Receptor Antagonist for Cognitive Impairment: From a Biological Concept to a Development Candidate

Abstract: Cognitive impairment or deficit is an inclusive term to describe any characteristic that acts as a barrier to the cognition process. More than 16 million people in the United States are living with cognitive impairment. Currently, no cognitive impairment drugs or other treatments are specifically approved by the Food and Drug Administration (FDA), although physicians sometimes prescribe cholinesterase inhibitors. These, however, aren't recommended for routine treatment because they don't appear to provide lasting benefit. H3 receptor (H3R), a pre-synaptic GI/O protein-coupled auto-receptor, is widely expressed in the mammalian brain, particularly in areas involved in cognitive processes and arousal, such as the cerebral cortex, hippocampus, basal ganglia, and hypothalamus. Blockade of H3R with selective antagonists/ inverse agonist is hypothesized to increase the synthesis and release of histamine and other neurotransmitters involved in alert and cognitive functions. We are interested in discovery and development of a novel, potent, selective, and orally and CNS-penetrable H3R antagonist/ inverse agonist for treatment of cognitive impairment associated with AD and Schizophrenia. This presentation will describe our medicinal chemistry efforts towards this goal, beginning with biological concept through HTS and finally DC selection. Biographical Sketch: Zhongli Gao received his B. Sc. in Chemistry in 1982 and M. Sc. in Physical Organic Chemistry in 1984, both from Lanzhou University, and his Ph. D. in Synthetic Organic Chemistry from City University of New York in 1993, where he worked with Professor Berkowitz on the total synthesis of taxol. He pursued his postdoctoral work on the total synthesis of Spinosyn A with Professor Paquette at Ohio State University thereafter. From 1995 to present, he has been working at Sanofi. He is currently a Lead Investigator II and Project Team Leader in Medicinal Chemistry - LGCR with research interests in design and synthesis of small molecule ligands for GPCR and ion channels, and enzyme inhibitors and activators.