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SUNDAY, APRIL 23

Pre-Conference Symposium
ENCODED COMPOUND LIBRARIES
Focusing on Encoded Small Molecule Library Synthesis
(Separate Registration Required)
Please visit www.healthtech.com/2006/ecl/index.asp for details.

MONDAY, APRIL 24

7:30am Conference Registration

NOVEL SYNTHETIC STRATEGIES
FOR COMPOUND LIBRARY DEVELOPMENT

8:30 Chairperson’s Remarks
Christoph Huwe, Ph.D., Senior Scientist, Medicinal Chemistry, Schering AG

8:40 Refining Workflows and Automation Platform Towards Enhanced Hit-to-Lead Support
Christoph Huwe, Ph.D.
Traditionally Hit-to-Lead chemistry at Schering was driven by manual-single or manual-parallel synthesis focusing on few analogs, compared to an automated synthesis driven early optimization approach currently pursued. This change in strategy required a number of adaptations with regard to workflows, automation platform, and in-house reagent collection, both within the Hit-to-Lead team and the Automated Medicinal Chemistry group. These changes include pragmatic library design approaches, increased utilization of outsourcing to strengthen the proprietary building block portfolio, and refinement of workflows and automation platform to support higher flexibility and shorter response times.

9:10 Novel Synthesis of Cyclic Sulfamides and Sulfonamides: Access to Pharmacophores
Sherry Chemler, Ph.D., Assistant Professor, Chemistry, University at Buffalo, SUNY 
Cyclic sulfamides and sulfonamides are promising leads for protease inhibitors, for example HIV protease and beta-secretase (Alzheimer’s disease). Herein is reported the diastereoselective synthesis of such scaffolds via novel, diastereoselective copper carboxylate promoted carboamination and diamination reactions.

9:40 The Scope of Polymer-Supported Mukaiyama Reagent for the Preparation of Solution-Phase Libraries
Stefano Crosignani, Ph.D., Combinatorial Chemist, Research and Pharmaceutical Development, Chemistry Department, Serono Pharmaceutical Research Institute 
A polymer-supported version of the popular Mukaiyama reagent (2-chloropyridinium iodide) was prepared in one easy step from commercially available Wang resin. This reagent could be used to promote the coupling of carboxylic acids and amines or alcohols to give the corresponding amides or esters with high yields and high purities without need for any purification of the product. The complete chemoselectivity of the coupling of carboxylic acids with b-aminoalcohols to give exclusively N-acylation was exploited in order to develop a practical one-pot protocol for the preparation of libraries of 2-oxazolines. Polymer-supported tosyl chloride was used for the cyclision step in order to obtain 5-unsubstituted oxazolines. However, when polymer-supported 2-fluoropyridinium triflate was used for the cyclisation, 5-substituted 2-oxazolines could be obtained, something which was not possible using the currently available polymer-supported reagents. 

10:40 AMRI's Select Compound Screening Library: Design and Synthesis
Dr. John Quinn, Sr Research Chemist, Medicinal Chemistry, Albany Molecular Research Inc.
AMRI s Select Compound Screening Library is a collection of approximately 48,000 medicinally relevant small molecules constructed around 80 core scaffolds. We will discuss the criteria for library design and synthesis for inclusion in the collection. Several case studies will be presented that highlight both the optimization of the chemical synthesis and the physiochemical properties of the libraries.

10:55 LeadDiscovery™ - Knowledge Enabled Chemistry in Library Design 
Michael Lawless, Ph.D., Molecular Design Senior Team Leader, Tripos Discovery Research Center 
Tripos Discovery Research is engaged in the design and development of novel chemistry platforms for use in the areas of GPCR’s and Kinases. Using state-of-the-art proprietary software and tools, Tripos’ experienced medicinal chemists have identified and synthesised multiple novel scaffolds and subsequently shown both potency and selectivity for the validated targets. In this presentation we will outline recent developments of Tripos’ Knowledge-Driven Chemistry Process and its application in LeadDiscovery(TM).

11:10 Privileged Scaffolds: Novel Inhibitors of Cancer and Autoimmune/Inflammatory Targets
Robert DeSimone, Ph.D., President, Privileged Discovery Partners 
Privileged Discovery Partners, LLC has developed an efficient method of hit identification and subsequent hit-to-lead optimization. PDP’s approach utilizes a novel set of Privileged Scaffolds™ coupled with a propriety method of library design and synthesis. PDP’s unique approach is being employed to identify novel small molecule inhibitors of targets in cancer and autoimmune/inflammatory diseases. PDP’s approach and results will be discussed.

11:45 Determination of Additivity in Combinatorial Libraries and Implications in the Interpretation of SAR; a CCK1 Antagonist - Case Study 
Dr. Laurent Gomez, Scientist, Chemistry, Johnson & Johnson Research & Development L.L.C. 
We are making use of additivity analysis to guide our SAR work in the CCK1 antagonist program that resulted in a clinical candidate for pancreatitis. We use this analysis to guide our decisions regarding the further use or discontinuation of matrix library synthesis and to gain better understanding of how molecules bind to the target. This analysis is generally applicable to any program in which combinatorial libraries are made. My group has presented similar studies at Gordon Conferences and other meetings and been well received.

1:15 Session Break

OPTIMIZATION of HIGH-THROUGHPUT SYNTHETIC METHODS, TECHNOLOGY and INNOVATIVE SEPARATION STRATEGIES 

1:30 Chairperson’s Remarks
Daryl R. Sauer, Ph.D., Senior Group Leader, High-Throughput Organic Synthesis, Global Pharmaceutical Research and Development, Abbott Laboratories

1:40 Technology Watch

Focused Libraries ­ Recent Advances & True Successes Richard Hill, Ph.D., Department Head, Discovery Products, BioFocus Discovery Ltd, A Galapagos Company Since 1999, BioFocus has pioneered the field of pre-designed focused libraries, specifically targeting kinases, GPCR’s and ion channels. These libraries have been proven to deliver real benefits providing SAR derived directly from initial screening, together with potent and selective hits. These results coupled with robust synthetic and purification techniques, combine to rapidly accelerate early stage drug discovery. Several recent examples will be presented with screening results from our highly successful SoftFocus® brand.

1:55 Novel Trends in Focused Library Design: From Concept to Efficacy 
Alex Kiselyov, Ph.D., Executive Vice President of R&D, ChemDiv, Inc.
We introduce the concept of focused diversity that describes the selection of compounds that have been annotated against orthogonal biological targets. A focused diversity set (FDS, 3000 compounds) was assembled from pre-screened target- (Kinases, GPCR’s, etc.) or pathway-biased selections, as well as from the non-partial selections including rule-of-three, peptidomimetics and natural product-based libraries. FDS yielded high quality hits when screened against “difficult” targets with limited or no structure/ligand information, for example modulators of Hh signaling pathway. In addition, we successfully used the set in the identification of novel chemotypes for binding to “conventional” targets, including Kinases and GPCR’s.

2:10 Platform Library Science, an Initiative to Build and Structure Lilly’s Screening Compound Collection
Author: Horst Hemmerle, Ph.D., Director, Lead Generation Technologies, Lilly Research Laboratories, Lilly Corporate Center
Presenter: Dr. Horst Hemmerle, Director Lead Generation Technologies, Lead Generation Technologies, Eli Lilly & Co.
Over the last decade a number of rules-based methods have been established to increase success rates of Lead Generation efforts. As a part of this learning knowledge-based library design is meanwhile a component of all strategies for building screening collections. An overview about Lilly’s approach to enrich its compound collection will be discussed. 

2:40 Recent Advances in High-Throughput Organic Synthesis for Drug Discovery
Dr. Daryl R. Sauer, Senior Group Leader, High-Throughput Organic Synthesis, Global Pharmaceutical Research and Development, Abbott Laboratories 
Parallel synthesis has proven to be a highly effective and increasingly popular tool in organic and medicinal chemistry. The use of automation to accelerate the lead development and optimization processes in pharmaceutical research is a logical and useful extension of this technology. In the High-Throughput Organic Synthesis group at Abbott Labs we utilize microwave-accelerated synthesis, standardized reaction protocols, polymer assisted solution phase chemistry, flow synthesis and automation in an effort to create libraries of analogs rapidly and efficiently. This presentation will detail reaction protocols, chemical transformations and automation platforms that have been developed and utilized for this purpose in the drug discovery process at Abbott Laboratories.

3:10 Microchemistry Approach to Hit-to-Lead and Lead Optimization Projects
Olga Issakova, Ph.D., Executive Vice President, Nanosyn
For the past ten years numerous efforts have been made to accelerate drug discovery through implementation of advances in X-ray, NMR, computational techniques, etc. However, since traditional medicinal chemistry remains the primary driving force behind the successful generation of drug candidates, there is a great demand for innovative technologies capable of increasing the efficiency and productivity of medicinal chemists. At Nanosyn we utilize microchemistry library generation technology to empower medicinal chemistry on the stage of lead optimization. Features of the platform include use of microwave-assisted synthesis, microgram quantities for IC50 determination, CLND quantitation in screening buffer, etc. This presentation will use two case studies to highlight the benefits of microchemistry for lead optimization projects. Special emphasis will be placed upon novel approaches to library design using microchemistry.

4:05 Soluble Polymers in Synthesis - Homogeneous Reactions/Biphasic Separations
Dave Bergbreiter, Ph.D., Eppright Professor of Chemistry, Department of Chemistry, Texas A&M University 
Our work employs quite a different strategy than is used with synthesis on solid phase ­ focusing on reactions that are completely homogeneous where efficient separations of products from catalysts/reagents are achieved in a second biphasic separation. Such separations are typically effected by either gently warming a solution to precipitated a polymer-bound product/catalyst/reagent (with a solid/liquid separation) or by perturbing a solvent mixture to produce two separable liquid phases that selectively contain the soluble polymer-bound species and the products (or byproducts). 

4:35 Semantic Compound Library and Semantic Web Technology for Drug Design and Synthesis
Talapady Bhat, Ph.D., Project Leader, Biotechnology, National Institute of Standards & Technology 
Screening of chemically feasible and structurally relevant and biologically significant compounds that possess basic characteristic features of an active drug are at the core of rational structure-based drug design. Existing library of both 3-D structures of enzyme/drug complexes and 2-D structures of both successful and not so successful drugs narrate the secret stories of drug design work carried out in the past. I will present efficient and novel techniques to curate, integrate, and disseminate this knowledge. The talk will focus on the use of chemical ontology and semantic web technology for compound libraries. In this method, the library of compounds are organized and cross-indexed using biologically and structurally relevant and chemically stable fragments to enable queries that are semantically aware from the terminology of drug design.

5:05 Library Synthesis in Continuous Microreactors: Enabling Multi-Step Diversification with Unrestricted Access to Synthesis Intermediates
Thomas Schwalbe, Ph.D., CEO, MRSP - Micro-Reactor Systems Provider, Inc. 
We will report on an integrated microreactor platform, the SEQUOS, and perform library synthesis and optimizations at a scale of mg to gramme under identical reaction conditions. A case study on the synthesis of a library of Ciprofloxacin analogues diversifies the core theme in two positions. The sequential synthesis of such compounds in a continuous regime grants favorable access to higher quantities of diversified building blocks in discovery.

5:30 Networking Cocktail Reception

Tuesday, April 25

METHODOLOGIES FOR THE DESIGN AND SYNTHESIS OF DIVERSITY LIBRARIES: 2006 Chemical Methodologies and Library Development (CMLD) REPORTS 

8:45 Chairperson’s Remarks
Jeff Aubé, Ph.D., Professor of Medicinal Chemistry and Director, KU-CMLD Center, University of Kansas 

8:55 Synthesis of Small Molecule Libraries with Functional and Structural Diversity
Stefan Werner, Ph.D., Associate Director, UPCMLD, University of Pittsburgh 
The University of Pittsburgh Center for Chemical Methodologies and Library Development (UPCMLD) applies methodologies that were developed in our Department to compound library synthesis. For an efficient library synthesis, time consuming and labor intensive purification operations have to be avoided. Reactions and purifications should be performed in a parallel fashion. Therefore, polymer or silica bound reagents and SPE scavenging and separation techniques are used frequently in our library syntheses. To further accelerate the synthesis workflow, reactions and scavenging steps are carried out in an automated microwave reactor. This talk will focus on the application of divergent multi component reactions (DMCRs) to the synthesis of cyclopropyl and E-alkene dipeptide isostere libraries. Skeletal diversity can be introduced with transition metal catalyzed carbon-carbon-bond forming reactions. This concept was demonstrated in libraries of 3-pyrrolines and tricyclic pyrrole-2-carboxamides. Another focus will be the development and application of a parallel microreactor, allowing not only the fast optimization of reaction conditions, but also the high-throughput synthesis of small molecule libraries.

9:25 Expanding Diversity Through Chemical Methodology
Aaron Beeler, Ph.D., CMLD-BU Assistant Director, Department of Chemistry, Boston University 
The Center for Chemical Methodology and Library Development at Boston University (CMLD-BU) is focused on discovery and development of new reaction methodologies that may be applied to the synthesis of complex molecule arrays. This talk will focus on examples of stereo-controlled synthesis to address new areas of chemical space and novel methods for reaction discovery. 

9:55 Networking Coffee Break, Poster and Exhibit Viewing

10:25 Macrocycloaddition Approaches for the Synthesis of Conformationally Restricted Small Molecules
Ryan E. Looper, Ph.D., Postdoctoral Fellow, Department of Chemistry and Chemical Biology, HU-CMLD and the Broad Institute of Harvard University and MIT
The mission of Harvard CMLD center is to develop efficient, general, state-of-the-art methodologies for the synthesis and rapid identification of new compounds capable of perturbing biological systems. Following our recent correlations of stereochemical arrays with biological outcomes, this talk will focus on the efficient synthesis of stereochemically rich macrocyclic ring systems. 

10:55 Libraries Inspired by, but not Beholden to, Peptide Structures
Jeff Aubé, Ph.D., Professor of Medicinal Chemistry and Director, KU-CMLD Center, University of Kansas 
One approach to peptide-based drug design has been to identify important classes of secondary structures and to mimic them with carefully designed heterocycles. Work in this laboratory has focused on both this class approach (beta and gamma turn mimics) and on heterocycles that have elements of peptide structures (amide bonds, side chains) but that are not slavishly designed along the lines of particular conformations. Examples of libraries based on both types of scaffolds will be described.

11:50 Chair's Closing Remarks
Jeff Aubé, Ph.D.

12:00pm Close of Conference