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SCIENTIFIC ADVISORY BOARD:
Christoph M. Huwe, Ph.D., Senior Scientist, Medicinal Chemistry, Bayer Schering Pharma AG
David Nirschl, Ph.D., Research Group Leader, Synthesis & Analysis Technology Team, Pharmaceutical Research Institute, Bristol-Myers Squibb Company
Brian A. Moloney, Ph.D., Vice President, Library Synthesis & Compound Management, Evotec
Guillermo A. Morales, Ph.D., Director of Chemistry, Semafore Pharmaceuticals, Inc.

Sunday, May 13

4:00 - 6:00 pm Conference Early Registration

Monday May 14

7:00 am Registration and Morning Coffee

8:00 Welcoming Remarks from Conference Director
Shelley Amster, Cambridge Healthtech Institute

8:05 Chairperson’s Opening Remarks
David Nirschl, Ph.D., Research Group Leader, Synthesis & Analysis Technology Team, Pharmaceutical Research Institute, Bristol-Myers Squibb Company

8:15 Success by Design
Richard Roberts, Ph.D., Senior Medicinal Chemist, Almirall Prodesfarma, S.A.
A good lead molecule will give your optimization program a tremendous headstart. A poor lead molecule can ultimately be very costly in time and recourse due to inherent weaknesses. This presentation will outline the collaboration between Almirall and Evotec for the design and synthesis of libraries for our lead finding collection, highlighting aspects of the process, molecular design and synthesis, some of the lessons learned and the successes earned. This presentation will include information about improved strategies to address current bottlenecks and what are the alternatives to automation.

8:45 Design, Construction and Validation of an Automated Flow Hydrogenation Apparatus
Bruce Clapham, Ph.D., Associate Research Investigator, High-Throughput Organic Synthesis, Global Pharmaceutical Research and Development, Abbott Laboratories
In order to provide high level project support to Abbott’s medicinal chemistry programs, our high-throughput organic synthesis (HTOS) group relies on the use of cutting edge technologies integrated with often custom built automation. The ThalesNano H-Cube represents a revolution in synthetic chemistry since it enables hydrogenations to be performed easily and efficiently in a flow through manner, using pre-packaged catalyst cartridges. However, at the time of its release, this instrument was supplied solely as a stand alone flow reactor- at Abbott, we have constructed an automated H-Cube platform and validated its application in the synthesis of compound libraries. The importance of this emerging flow hydrogenation technology cannot be understated since it brings chemistries to the fingertips of high-throughput chemists that were previously unavailable.

9:15 A Parallel-Synthesis-Friendly Approach to Highly Complex Chemical Structures- Post Modifications on Multicomponent Reactions
Irini Zanze, Ph.D., Group Leader, R4CP, Abbott Laboratories
In this talk, we will describe the development of synthetic methodology that can be easily adapted for HTOS. The reaction sequences involve the combination of an MCR with an intramolecular transformation to produce highly complex structures. Examples of applications of these methodologies to automation will also be provided. 

9:45 Efficiency-Driven Process for the Parallel Synthesis of Drug-like Molecules
Eduard Felder, Ph.D., Director of Chemical Core Technologies, Nerviano Medical Sciences Srl.
Combinatorial derivatization of heterocyclic scaffolds represents a rich source of novel drug-like compounds. This poses the question on how far the validation of synthetic protocols should be carried on before the production of compound libraries is initiated. The advances in high-throughput purification and quantitative analysis of microsamples (CLND Chemiluminescent Nitrogen Detection) provide the option to enter the library production stage even with protocols associated with highly variable yields. These techniques are used to restore impeccable purity and correct concentration on samples originating from arrays of qualitatively inhomogeneous crudes. The presentation illustrates applications to the discovery of powerful kinase inhibitors from libraries containing inhibitors with specific profiles as tested on a panel of kinase targets and subsequently optimized to a clinical candidate

10:15 Networking Coffee Break

10:45 Stereoselective Synthesis of Complex Heterocycles That Modulate Transcription
Jared Shaw, Ph.D., Institute Fellow, Chemical Biology Program, Broad Institute of
Harvard and MIT
The synthesis of a diverse library of lactam carboxamides from the cycloaddition reaction of imines with anhydrides is described. The use of different cyclic anhydrides produces different core structures with functional group, skeletal, and stereochemical diversity. These compounds were included in a screen for inhibitors of the binding of the HOXA13 transcription factor to its target sequence of DNA. Two structurally similar compounds were identified from the described library, and one was found to inhibit binding of this transcription factor with an IC50 of 6.5mM. This study demonstrates the value of synthesizing libraries of structurally complex molecules as a starting
point for discovering inhibitors of protein-macromolecule interactions.

11:15 Centralized Rapid Analog Library Synthesis: Challenges and Strategies
David Nirschl, Ph.D., Research Group Leader, Synthesis & Analysis Technology Team, Pharmaceutical Research Institute, Bristol-Myers Squibb Company
The past several years have seen a drastic increase in interest for focused, lead optimization libraries intended to directly impact specific drug discovery programs by providing rapid access to structureactivity relationship data. To meet these changing needs, which in the past were more focused on lead discovery rather than lead optimization, we have established small, expert teams comprised of synthetic chemists, analytical chemists and technologists. The teams have implemented novel solutions to problems such as reagent management and library turnaround time by translating and implementing Lean manufacturing concepts. Looking to the future, we will be challenged by increasingly complex chemistries as well as rigorous demands for compound purity, compound characterization and overall success rates.

11:45 Technology Watch (Sponsorship Available)

12:00 LUNCHEON TECHNOLOGY WORKSHOP

Sponsored by

Rapid Compound Production: Microwave-Assisted Synthesis, Work-up and Purification
Farah Mavandadi, Ph.D., Product Manager, BIOTAGE in Salon A&B

1:00 Session Break

1:30 Chairperson’s Remarks
Christoph M. Huwe, Ph.D., Senior Scientist, Medicinal Chemistry, Bayer Schering Pharma AG

1:40 A Flexible Response Library Production Approach
Christoph M. Huwe, Ph.D.
In the presentation, a collaborative workflow for the synthesis, purification and reformatting of compound libraries is discussed. In this approach, the goal of a balanced mixture between flexibility and standardization is achieved by utilizing complementary automated synthesizer systems in order to be able to provide a large diversity of chemotypes, HPLC-MS systems that can adapt to a variety of purification problems, and a highly automated robotic reformatting system supporting a standardized compound submission scheme. The advantages and challenges related to this approach are outlined.

2:10 Greener Chemical Syntheses via Mechano- Chemical Mixing or Using Microwave Irradiation in Eco-Friendly Media
Rajender S. Varma, Ph.D., U. S. Environmental Protection Agency, National Risk Management Research Laboratory, Sustainable Technology Division
A simple approach to rapid organic synthesis or transformation using ‘greener’ reaction conditions, especially in the context of multicomponent condensation reactions that are amenable to building of libraries of compounds, is very desirable. A variety of eco-friendly reactions based on the mechanochemical mixing of neat reactants or the mild exposure of reactants to microwave irradiation in benign media such as water or polyethylene glycol for rapid one-pot assembly compounds will be described. Similar strategy for the generation of metallic or bimetallic nanomaterials in environmentally-friendly medium or in crosslinked form as nanocomposites will be presented that may find safer application in chemical synthesis.

3:15 Technology Watch
To be Announced
Dr. Hung-Yuan Cheng, Applications Scientist, Eksigent Technologies LLC

3:30 Networking Refreshment Break

4:00 Improvements in the Synthesis and Purification of Small Molecule Libraries- MAOS and Reagents/Scavengers on Solid Support
Stefan Werner, Ph.D., Research Assistant Professor, University of Pittsburgh Center for Chemical Methodologies & Library Development (UPCMLD), Associate Director, University of Pittsburgh
The University of Pittsburgh Center for Chemical Methodologies and Library Development (UPCMLD) applies methodologies that were developed in our Department to library synthesis. Microwave-assisted organic synthesis (MAOS) is used frequently for solution phase chemistry as well as for resin bound reagents and scavengers. The use of microwave reactors speeds up reactions and makes high temperature reactions much safer. Microwave irradiation, therefore, completely replaced the traditional oilbath in our laboratories. Many chemists in the drug discovery process see purification as the bottleneck. Traditional chromatography is a very time consuming and expensive purification strategy. Polymer, fluorous or silica bound reagents and scavengers offer a much faster purification technique, providing compounds in purities often above 95%. This talk will discuss the application of microwave chemistry in several mid-size solution phase small molecule libraries as well as the use of resin bound reagents and scavenging techniques to accelerate purification.

4:30 Panel Discussion
Improving the Process Through Improved Technology- Compare and contrast

• Is there still a need for new library synthesis technologies?

• What new technologies are out there and which can help to optimize the library production process?

• What level of automation is optimally supporting the workflow?

• When to use polymer-bound reagents/scavengers, when silicabound reagents/scavengers?

• Are fluorous reagents/scavengers alternatives to polymer- and silica-bound reagents/scavengers?

• What are the advantages/disadvantages?

• Are there techniques that are not suitable for automatization and if so: how to substitute them?

• What's the role of flow-chemistry in high-throughput synthesis? Does it have a future?

• MAOS changed the way we are performing High Throughput Synthesis within the last 10 years. What's the technology for the next 10 years?

Moderator: TBA
Panelists:
Eduard Felder, Ph.D., Director, Chemical Core Technologies, Novartis Medical Sciences
Christoph M. Huwe, Ph.D., Senior Scientist, Medicinal Chemistry, Bayer Schering Pharma
David Nirschl, Ph.D., Research Group Leader, Synthesis & Analysis Technology Team, Pharmaceutical Research Institute, Bristol-Myers Squibb Company
Stefan Werner, Ph.D., Research Assistant Professor, University of Pittsburgh Center for Chemical Methodologies & Library Development (UPCMLD), Associate Director, University of Pittsburgh

5:30- 7:00 Grand Opening Reception and Poster Viewing in The Exhibit Hall

Tuesday, May 15 

7:30am Interactive Roundtable Discussions - Road Blocks to Progress

Table 1: Incorporation of Physicochemical and Pharmacokinetic Issues in HTOS for Lead Optimization
Moderator: Guillermo A. Morales, Ph.D., Director of Chemistry, Semafore Pharmaceuticals, Inc.

Table 2: Building Block Logistics: How to Optimize Availability and Diversity?
Moderator: Christoph M. Huwe, Ph.D., Senior Scientist, Medicinal Chemistry, Bayer Schering Pharma AG

Table 3: Successful Small Scale Purification Techniques Using Natural Products
Moderator: Ying Wang, Ph.D., Laboratory Head, Natural Product Chemistry, DT/NPU, Novartis Institutes for BioMedical Research, Novartis Pharma Inc.

9:00 Chairperson’s Remarks
Guillermo A. Morales, Ph.D., Director of Chemistry, Semafore Pharmaceuticals, Inc.

9:15 Research Bottlenecks in Small Biotech: Synthesis versus Purification
Guillermo A. Morales, Ph.D., Director of Chemistry, Semafore Pharmaceuticals, Inc.
Biotech and big pharma share a common goal: discover and optimize new biologically active compounds to graduate them into new APIs and move them into the clinic. However, the paths towards this goal for biotech and big pharma are quite different. Big pharma has deeper pockets allowing the implementation of a more favorable infrastructure where researchers are provided with the necessary tools and equipment to achieve quickly their research goals. On the other hand, biotechs (which usually are in start-up phase and are not profitable for a significant period of time) face serious dilemmas and limitations to invest or allocate the necessary resources for their research programs. In drug discovery synthesis and purification go hand to hand. Combinatorial/parallel medicinal chemistry provides the means to quickly synthesize analogs for SAR elucidation and optimization. However, without purification support the whole process significantly slows down. This talk will cover several scenarios that biotechs face to achieve the right balance between synthesis and purification for drug discovery.

9:45 High-Throughput Organic Synthesis and Purification: The Tie-2 Story
Michael J. Chen, Ph.D., Principal Scientist, Cancer Chemistry, Pfizer Global R&D Groton Labs
High-throughput organic synthesis and purification have been effectively deployed to facilitate the progression of an oncology discovery project targeting the angiogenic Tie-2 receptor tyrosine kinase. The project team adapted a streamlined and flexible medicinal chemistry analoging approach, which included concerted efforts in template/intermediate preparation, robust analog synthesis with automated HPLC sample purification and/or resin-bound reagents. These efforts led to the identification of a series of potent and selective ketopyrrolopyrimidines and culminated the discovery of PF- 371989 with robust antiangiogenic activity and tumor growth inhibition. This presentation will offer a retrospective analysis of various strategies and tactics of high-throughput synthesis of the Tie-2 chemistry team.

10:15 Networking Coffee Break, Poster and Exhibit Viewing

10:45 Developing Technologies for Reaction Discovery
John Goodell, Ph.D., Post Doctoral Scientist, Center for Chemical Methodology and Library Development (CMLD-BU), Department of Chemistry, Boston University
Discovery of novel chemical transformations has emerged as a significant challenge for generating diverse compound libraries. The CMLD-BU has developed multidimensional reaction screening in efforts to identify reactions affording novel chemotypes. An overview of these projects and the investigation of microfluidic technology to enable high-throughput reaction screening will be discussed.

11:15 HT-Purification of HTOS Libraries and the Production of Highly Purified Compounds in Drug Discovery
John J. Isbell, Ph.D., Director Bioanalytical Chemistry, Genomics Institute of the Novartis Research Foundation
My talk will cover HT-purification of HTOS libraries, development of a HT-purification process and how the purification needs and systems were then adapted to meet the changing needs of drug discovery projects as they progressed to preclinical candidates.

11:45 Closing Panel Discussion
Available Purification Technologies: Have They Reached Their Pinnacle? What's Next?

• When is parallel/mass compound purification worth the effort (or not)?

• How do we find the right balance between purification of intermediates versus final products?

• Between what, when, and why? MUXS versus SFC versus HPCL

• What are "minimum purity" trends over the past several years, for either lead discovery or lead optimization compounds?

• Are scientists investing in automated synthesizers, or are they a thing of the past?

Moderator: TBA
Panelist:
Michael J. Chen, Ph.D., Principal Scientist, Cancer Chemistry, Pfizer Global R&D Groton Labs
John Goodell, Ph.D., Post Doctoral Scientist, Center for Chemical Methodology and Library Development (CMLD-BU), Department of Chemistry, Boston University
John J. Isbell, Ph.D., Director Bioanalytical Chemistry, Genomics Institute of the Novartis Research Foundation

11:55 Chairperson’s Conclusions and Closing Remarks

12:00 Close of High-Throughput Organic Synthesis & Purification Conference