Keynote Presentations:  Microwave-Assisted Organic Synthesis   February 27, 2003 · Hilton La Jolla Torrey Pines · La Jolla, California Organic Synthesis Floating on Hot Water Dr. K. Barry Sharpless,  The Scripps Research Institute Microwave-Assisted Heterocyclic Synthesis Dr. Alan R. Katritzky, University of Florida Sponsors:

Frustration with the lack of drugs entering the market has forced the pharmaceutical industry to examine how libraries are designed and synthesized. Emphasis has shifted from making large combinatorial libraries to smaller, more target-focused libraries, filtered to exclude non-drug or non-leadlike entities. This has been facilitated largely by increased knowledge of biological target structure, in conjunction with advances in computational tools. Combichem techniques are now being used more frequently in medchem projects and yielding results in lead discovery and optimization. Efforts to produce diverse natural product-like libraries in the hope of finding compounds that will be more effective in the clinic are also gaining a great deal of attention. Compound storage and stability are critical issues for many organizations that handle large compound collections. All of these topics will be discussed at length during this event. This conference will include a one-day special event showcasing results from microwave-assisted synthesis in organic, medicinal, and combinatorial chemistry. Presentations will be given by key industrial and renowned academic players in this new exciting field.

Advisory Committee

To read related articles on Advancing Library Design  and Organic Synthesis from Current Drug Discovery's  March 2002 issue,  click here  Sponsoring Publications: Advances in Lead Optimization Current Drug Discovery Drug Discovery and Development Elsevier Science Genome Research Kluwer PharmaGenomics Physiological Genomics Wiley-VCH Web Partners: Combichem.net HTScreening.net Processdevelopment.net

Dr. Prabhat Arya, National Research Council of Canada Prof. Hicham Fenniri, Purdue University Dr. Adam Golebiowski, Procter & Gamble Pharmaceuticals Dr. Timothy Herpin, Bristol-Myers Squibb Company Dr. C. Oliver Kappe, Karl-Franzens-University Graz Dr. Christopher A. Lipinski, Pfizer Global Research and Development Dr. Aubrey J. Mendonca, Polymer Laboratories Inc. Dr. David Portlock, Procter & Gamble Pharmaceuticals Prof. Herbert Waldmann, Max-Planck-Institut für Molekulare Physiologie

 

1:30-2:00 Preconference Tutorial Registration

2:00-5:00 Preconference Tutorial: Electronic Notebooks

Sponsored by:

Dr. Rich Lysakowski, Executive Director/Chief Science and Technology Officer, Collaborative Electronic Notebook Systems Association (CENSA) Collaborative Electronic Notebook Systems Association (CENSA) aids in the innovation, convergence, and integration of technologies for building Collaborative Electronic Notebook Systems (CENS) and more advanced systems for R&D team project data management, collaboration, and recordkeeping.

4:00-5:30 Early Conference Registration

7:30am Registration, Poster Setup, and Light Continental Breakfast

 

DRUGLIKE OR LEADLIKE IN LIBRARY DESIGN?

8:30 Chairperson's Opening Comments
Dr. Christopher A. Lipinski, Adjunct Senior Research Fellow, Pfizer Global Research and Development

8:40 Leadlike versus Druglike Combinatorial Libraries: Design and Chemistry Tradeoffs
Dr. Christopher A. Lipinski
Druglike libraries are those with the characteristics of a drug or a clinical candidate. Leadlike libraries are intended for HTS screening and allow for property changes that are inevitable to medicinal chemistry optimization of the initial screening lead. The successful production of a leadlike library involves conflicting tradeoffs in the library design itself, the assay screening dose, the library production chemistry success rate, the actual library computational profile, and the probability that medicinal chemistry can successfully optimize the initial lead.

9:10 Designing for Success: The Generation of Useful Leads with Small Molecule Libraries
Dr. Robert A. Goodnow Jr., Senior Research Leader, New Leads Chemistry Initiative, Combinatorial Chemistry, Hoffmann-La Roche, Inc.
In the increasingly demanding drug discovery environment, the value of a good lead cannot be overstated. Pharmaceutical companies have begun to populate compound collections with multiple, targeted small molecule libraries synthesized using combinatorial chemistry. Successful efforts to select, design, and synthesize such libraries for lead finding must address several critical aspects including target biasing, chemical diversity, library size, drug- and/or lead-likeness, and physical quality of the samples. This approach to lead generation illustrates not only a means of increasing the number of quality leads available for lead optimization but also a method to test library design ideas for validity and utility in a chemical genomics context.

9:40 Design of a Kinase-Biased Lead Generation Library
Dr. John A. Josey, Senior Director, Lead Generation, Array BioPharma
The integration of molecular modeling, conformational analysis, calculated physiochemical properties, robust and scalable synthetic chemistry, parallel synthetic techniques, and analytical chemistry in the design and execution of a kinase-biased lead generation library will be described. Emphasis will be placed on the design of unique and drug-like lead molecules, pragmatic synthetic schemes that allow for rapid follow-up of active compounds and the flexibility to probe alternate classes of targets with the lead generation library.

10:10 Refreshment Break

10:55 Properties That Influence the Oral Bioavailability of Drug Candidates
Dr. Kenneth D. Kopple, Consultant and Former Director, Cheminformatics, GlaxoSmithKline
Oral bioavailability measurements in rats for a sample of more than 1,100 drug candidates reveal that, independent of molecular weight, reduced molecular flexibility, measured by number of rotatable bonds, and low polar surface area (or total hydrogen bond count) are important predictors of good oral bioavailability. Although it is also observed that these properties do not correlate with rat whole body clearance rates, they do correlate with artificial membrane permeation rates. In the data studied, the observations suggest that compounds that meet only the two criteria of (1) fewer than 10 rotatable bonds and (2) polar surface area of less than 140 A2 (or 12 or fewer H-bond donors and acceptors) will have a high probability of good oral bioavailabililty in the rat.

11:25 An Alternative Approach to the Design of Pharmaceutical Screening Libraries
Dr. Ramaswamy Nilakantan, Wyeth-Research
Current strategies for screening-library design are mostly based on compound diversity. I will discuss an alternative approach that involves synthesizing relatively small numbers of analogs around a set of "druglike" scaffolds.

11:55 Panel Discussion

12:25 Lunch on your own (workshop sponsorship available)

 

DIVERSITY-ORIENTED SYNTHESIS: NATURAL PRODUCTLIKE LIBRARIES

1:55 Chairperson's Comments
Dr. Prabhat Arya, Chemical Biology Program, Steacie Institute for Molecular Sciences, National Research Council of Canada

2:05 Libraries for Enchanced Drug Discovery: Combinatorial Chemistry-Past, Present, and Future
Dr. Neerja Bhatnagar, Head, Natural Product Chemistry, DI&A/Chemistry/ High Performance Unit, Aventis
The following topics will be discussed: (1) the importance of library design, (2) information rich structures for specific targets, (3) the importance of natural product analogs for better understanding of targets, and (4) new-generation libraries.

2:35 Diversity-Oriented Asymmetric Synthesis of Indole and Quinoline-Based Polycyclic Derivatives
Dr. Prabhat Arya
Inspired by bioactive natural products, our goals are (i) to develop asymmetric synthesis-derived diversity-oriented synthesis and (ii) to use the libraries of natural product-like small molecules as probes to modulate the functions of protein targets. Although combinatorial chemistry is well accepted in the medicinal community because it allows the synthesis of several compounds in a parallel manner efficiently, the challenge now is to develop stereo- and enantioselective synthesis-based methods on solid phase to obtain fast access to complex, functionalized, natural product-like compounds. At present, with few exceptions, most combinatorial methods have been utilized in the synthesis of rather simple compounds, e.g., compounds bearing no stereogenic centers. The need for these efforts is growing constantly because of the rapid rise in emerging challenging biological targets from genomics and proteomics research.

3:05 Adventures in Diversity-Oriented Synthesis
Dr. David R. Spring, Department of Chemistry, University of Cambridge
The search for small molecules that modulate a biological pathway, without regard to any particular macromolecular target, requires screening high-quality collections of structurally diverse small molecules. The synthesis of such collections remains a major challenge to synthetic chemists. Recent strategies and results of our research in the synthesis of structurally diverse compound libraries using catalytic enantioselective reactions will be described. Also, the application of this library in the search for new antibacterial targets will be highlighted.

3:35 Refreshment Break

4:20 Combinatorially Driven Natural Product Synthesis
Dr. A. Ganesan, Department of Chemistry, University of Southampton
The design of combinatorial synthetic routes to biologically active natural products will be of increasing importance in the 21st century. Such projects offer new opportunities for target validation as well as lead discovery and optimization. The talk will cover recent illustrative examples from my group related to cyclic peptides and alkaloids.

4:50 Complementary Approaches to Synthetic and Biologically Derived Drug Discovery
Dr. Dwight Baker, Senior Director, and Dr. Cheryl D. Garr, Director, Business Development, Albany Molecular Research, Inc.
Eons of evolution and biological diversity have yielded a breadth of chemical diversity that is unparalleled in synthetic chemical libraries. To make effective use of this unique chemical diversity there must be a synergy between biological and synthetic chemical approaches at all steps from library building to lead optimization. Albany Molecular Research has built an integrated set of technologies which permit the utilization of any type of chemical diversity in the discovery process and move lead compounds forward in many parallel optimization and development schemes.

5:20 Panel Discussion

5:50-7:20 Networking Reception in the Exhibit Hall (Exhibit Hall Opening)

 

7:30am Light Continental Breakfast (workshop sponsorship available)

 

TARGET-FOCUSED LIBRARIES

8:30 Chairperson's Comments
Dr. Barry A. Bunin, President and Chief Scientific Officer, Libraria, Inc.

8:40 New Methods in Dynamic Combinatorial Chemistry
Dr. Benjamin L. Miller, Consortium Director, Pathogen Detection Center for Future Health, University of Rochester
Small-molecule libraries generated using reversible bond-forming reactions, termed Dynamic Combinatorial Chemistry, provide a potentially efficient and "bio-inspired" source of receptor-binding compounds. This talk will describe our efforts to expand the Dynamic Combinatorial Chemistry concept to new receptors, reaction types, and selection schemes.

9:10 A Fresh Look at the Value of the Free-Wilson Model: Applications to the Analysis of Combinatorial Library SAR
Dr. J. Guy Breitenbucher, Johnson & Johnson Pharmaceutical Research & Development
Additive QSAR models have been applied to many SAR problems since their conception by Free and Wilson in 1964. In this presentation we will discuss how combinatorial library data allows the chemist to reevaluate the utility of these additive QSAR models. We will present data from a number of programs which establish the utility of additive models in predicting changes in ligand binding mode to its target. We will also show that additive analysis of combinatorial libraries also helps determine the validity of regression models applied to these data sets.

9:40 Identification and Use of Privileged Substructures for Computationally Driven High-Throughput Lead Discovery
Dr. Cedric Merlot, Cheminformatics Scientist, Serono Pharmaceutical Research Institute
A novel computational method for rapid identification of privileged substructures associated with a compound's biological activity has been developed, implemented, and validated on various targets. The method is termed discrete sub-structural analysis (DSA). Use of privileged substructures combined with other tools such as virtual compound libraries is a basis for the rational design of highly diverse albeit focussed compound sets for high throughput screening. The method outperformed random-based screening strategies in almost every instance, sometimes by ratios of 90 to 1. Real-life case studies illustrating the use of the methodology in the identification of novel 7-TM receptor ligands, phosphatase inhibitors, ion channel blockers, and kinase inhibitors are presented. The underlying principles and development of automated, DSA-based virtual screening and analysis tools will also be presented through case studies.

10:10 Refreshment Break, Poster and Exhibit Viewing

10:55 Choosing the Appropriate Leads: What Properties Are Relevant?
Dr. Tudor I. Oprea, Director, Office of Biocomputing, and Professor of Biochemistry and Molecular Biology, University of New Mexico School of Medicine
Based on historical data regarding structures that served as medicinal chemistry leads in successfully marketed drugs, we discuss the appropriate choice of leads in the current drug discovery paradigm. Physico-chemical, pharmacokinetic and pharmacodynamic properties need to be appropriately balanced during this process.

11:25 Leveraging Exhaustive Gene-Family-Wide SAR with Predictive e-Screens for Data-Driven Drug Discovery
Dr. Barry A. Bunin
Libraria has captured exhaustive public domain SAR on entire gene family targets with a proprietary technology platform that helps one better identify valuable novel compounds than would otherwise be possible. Predictive e-screens were developed to rationally prioritize molecules for synthesis or purchase in an empirically driven approach based on huge amounts of target-specific information, including all major sources of public information. Three successful proofs-of-concept where novel, patentable chemotypes for kinase inhibition were rapidly discovered will be disclosed for the first time.

11:55 The Road to Urotensin-II Receptor Antagonists: Structure-Function Study of Urotensin-II, Assembly of a Receptor/Ligand Model, and Synthesis of Directed Libraries
Dr. William A. Kinney, Research Fellow, Johnson & Johnson Pharmaceutical Research & Development
Biological evaluation of synthetic derivatives of goby urotensin-II (U-II) has provided clues to the salient structural features required for stimulation of its G-protein coupled receptor. Based on this information, a plausible U-II receptor/ligand complex was constructed using molecular modeling. The W-K-Y pharmacophore has been used as a guide for focused library generation and HTS lead optimization.

12:25 Lunch in Exhibit Hall

 

SOLUTION-PHASE SYNTHESIS

1:55 Chairperson's Comments
Dr. Michael G. Organ, Professor, Department of Chemistry, York University

2:05 Designing Novel Organocatalytic Asymmetric Multicomponent Reactions
Dr. Benjamin List, Assistant Professor, The Scripps Research Institute
The diversity generating potential of multicomponent reactions (MCRs) has been recognized and their utility in preparing libraries to screen for functional molecules is well appreciated. As more and more pharmaceuticals become chiral nonracemic molecules, catalytic asymmetric methodologies gain in importance. In this lecture we outline our strategy of merging the two disciplines in the development of novel organocatalytic asymmetric multicomponent reactions.

2:35 Design and Synthesis of N-Substituted Glycyl 2-Cyanopyrrolidines as a New Class of DPP-IV Inhibitors
Dr. John A. Brinkman, Senior Scientist, Metabolic and Cardiovascular Department, Novartis Pharmaceuticals
Dipeptidyl peptidase IV (DPP-IV) is a post proline cleaving enzyme which catalyses the cleavage of dipeptides AA-Pro (AA = amino acid residue) fron the N-terminus of proteins. Inhibition of DPP-IV has been recognized as a mechanistic approach of potential value in the treatment of type 2 diabetes. Our work describes the design and synthesis of a new class of potent, selective and stable DPP-IV inhibitors. The synthesis focuses on the use of both resin-based and solution-based chemistry to incorporate various N-substituted glycines at the P2 position of the dipeptide inhibitor. Details of the structure-activity relationships associated with variations of the P2 position are highlighted.

3:05 The Use of Solid-Supported Reagents in Solution-Phase Parallel Library Syntheses
Dr. Michael G. Organ
The use of supported reagents, scavengers, and reaction work-up platforms will be discussed with respect to carrying out solution-phase high-speed synthesis. Application of these methods to diverse library syntheses will be presented.

3:35 Refreshment Break, Poster and Exhibit Viewing

4:20 Towards Nanoscale Computing Devices Made of Biomolecules
Prof. Ehud Keinan, Technion-Israel Institute of Technology, and The Scripps Research Institute
Electronic computers can only process data encoded electronically, yet data to many valuable computations occur naturally as biomolecules. For example, modern medicine often involves procedures that can be viewed as computational processes, with molecules sampled from a patient as input and drug molecules to be administered as output. We have recently presented the first nanoscale, programmable finite automaton that computes autonomously with all of its components, including hardware, software, input and output being biomolecules, mixed together in solution (Nature, 2001, 414, 430). Our next goal was to take the concept of molecular computing one step further and obtain computation outputs in the form of specific biological functions.

4:50 High-Throughput Synthesis of Heterocycles for Lead Discovery and Lead Optimization
Dr. Marcus Bauser, Senior Research Scientist, Bayer Pharma Research Centre, Bayer AG
Besides HTS and Genomics, Combinatorial Chemistry is one of the major contributors to Bayer's outstanding Pharma Research Platform. It allows the "production" of thousands of new drug like compounds needed for discovery and also refinement of biological activity. Unique druglike libraries prepared by parallel high-throughput derivatization in solution must meet the same quality standard in terms of purity as classically "hand-made" derivatives. Therefore efficient purification in high throughput is necessary to deliver these libraries to screening facilities in a timely fashion. Compound logistics and storage and data handling are also crucial in this process.

5:20 Panel Discussion

5:50 Close of Day 2

7:30am Light Continental Breakfast (workshop sponsorship available)

 

SOLID-PHASE SYNTHESIS

8:30 Chairperson's Comments
Dr. Aubrey J. Medonca, Vice President, Business Development, Polymer Laboratories Inc.

8:40 High-Throughput Organic Synthesis: Application and Library Design
Dr. Ben Munoz, Director of Medicinal Chemistry, Merck & Co., Inc.
The use of solid- and solution-phase chemistry for the generation of non-peptidic small molecule libraries has become common practice, in both industry and academia. The approach taken in our laboratories for the synthesis of such libraries has been to utilize an acyl-pyridinium complex on solid support. This novel approach, which we refer to as Resin Activation/Capture Approach or REACAP Technology, has been successful, providing a number of novel scaffolds for generation of such libraries. The synthesis of these libraries and their application to drug discovery will be described.

9:10 In Situ Coupling Strategies for Labile Amino Acids: The Development of b-Amino-Cyclopropanedicarboxylic Acids as 3-D Templates for Combinatorial Chemistry
Prof. Oliver Reiser, Department of Organic Chemistry, University of Regensburg
An in situ coupling strategy based on the N-Alloc protecting group for amino acids that are unstable in N-unprotected form is described, both, in solution as well as on solid phase. Based on this protocol, the combinatorial functionalization of b-amino-cyclopropanedicarboxylic acids became possible, being a conformationally constrained, three-functional amino acid with unique turn inducing properties. Moreover, peptide sequences that are difficult to prepare by standard Fmoc or Boc strategies because of competing diketopiperazine formation can be efficiently synthesized by the method discussed here.

9:40 Novel Synthetic Methods on Solid Phase
Dr. Thomas Ruhland, Principal Scientist, Department of Combinatorial Chemistry, Lundbeck
The solid phase synthesis of substituted phenylpiperazines with high pharmaceutical interest is descibed. Iron-assisted SNAr-reactions were performed for the first time on solid phase and a library of unsymmetrically substituted phenylpiperazines and phenyl-1,4-diazepanes was synthesised using this novel strategy. The scope of iron-assisted SNAr reactions on solid phase was investigated, and reactions of representative nucleophiles from group VI (O, S, and Se) and V (N and P) of the periodic table were examined. Decomplexation of resin-bound iron complexes was achieved using 1,10-phenanthroline under irradiation, thereby overcoming the notorious disadvantages of decomplexation observed using solution-phase chemistry.

10:10 Refreshment Break, Poster and Exhibit Viewing

10:55 Novel Applications of Organoboronates in Multicomponent Reactions and Solid-Phase Synthesis
Dr. Dennis Hall, Associate Professor, Department of Chemistry, University of Alberta
This presentation will describe our work on applications of organoboron chemistry to the development of multicomponent reactions and new strategies for combinatorial solid-phase synthesis involving supported boronic acids. The optimization of a novel aza[4+2]/allylboration process for the diversity-oriented synthesis of druglike polysubstituted piperidines will de described both in solution and on the solid phase. The use of diethylaminomethylpolystyrene (DEAM-PS) in the immobilization, derivatization, and resin-to-resin transfer reactions of arylboronic acids will also be described, as well as our most recent work in the use of DEAM-PS and boronic acids as convertible tags for phase-switch chemistry.

11:25 Comparing Solid Supports under Synthetically Relevant Conditions
Dr. Samuel Gerritz, Group Leader, Lead Synthesis, Bristol-Myers Squibb Company
During the past decade, solid-phase synthesis has emerged as a popular strategy for the generation of small molecule chemical libraries. Over this period, a wide variety of reactions have been exemplified on the solid phase, and a number of these studies have highlighted the difficulties encountered in transferring a reaction from solution to solid phase. Many of these difficulties can be attributed to limitations of the solid support; either chemical, in which case the solid support is not inert to the reaction conditions, or physical, in which case the physical properties of the solid support suppresses the desired reaction. This presentation will focus on the application of competition experiments to study the variables that influence the reactivity of a given solid support. While general conclusions remain elusive, these studies highlight the complex interactions that affect the course of a solid-phase reaction.

11:55 Metathesis Strategies to Diverse Heterocycles and ROM Oligomers as Tools for Organic Synthesis
Dr. Paul R. Hanson, Department of Chemistry, University of Kansas
The major goal of our research program is to develop new synthetic routes to structurally diverse phosphorus- and sulfur-containing small molecules and polymers that will serve as novel pharmaceutical and chemical agents. Our program focuses on the use of transition-metal catalyzed processes to generate an array of novel compounds. In particular, we have focused our attention on ring-closing metathesis (RCM) and ring-opening metathesis polymerizaton (ROMP) reactions as a means to produce novel cyclic small molecules, biopolymers, catalysts, and combinatorial tools. The small molecules are being evaluated for their ability to inhibit several protease and matrix metalloproteinase (MMP) enzymes implicated in cancer, arthritis, acquired immune deficiency syndrome (AIDS), osteoporosis, and other disease processes present in humans. In addition, we have also initiated a major program aimed at using ROMP en route to phosphorus- and sulfur-containing polymers. These polymers will serve as novel drug- and gene-delivery vehicles and new chemical delivery vehicles for the development of combinatorial purification strategies.

12:25 Lunch in the Exhibit Hall

COMPOUND STORAGE AND PURIFICATION

1:55 Chairperson's Comments
Dr. Christopher A. Lipinski

2:05 Development and Implementation of a High-Throughput Organic Synthesis (HTOS) Service for Drug Discovery
Dr. Daryl R. Sauer, Group Leader, High-Throughput Organic Synthesis Group, Abbott Laboratories
Parallel synthesis is widely employed in the hit-to-lead and lead optimization processes in the pharmaceutical industry. In order to expand the utilization of this technology throughout our drug discovery organization and improve overall efficiency, we have established a HTOS service group. This presentation will describe the development of optimized reaction protocols, SAR-based monomer collections, automated synthesis platforms, informatics, purification techniques, compound handling procedures, microwave synthesis capabilities, and the implementation and acceptance of this service at Abbott.

2:35 Meeting the Challenge of Modern Chemical Library Management
Dr. Dalin Nie, Head of Compound Management & Automation, Lead Discovery, AstraZeneca
With increasing screening demands and growing sample collections, the task of managing large corporate Chemical Libraries for optimal quality and maximum lifetime has become more challenging. At the same time, it has become even more essential for conservation of these limited resources. This presentation will focus on improvements in inventory and storage of a compound library to preserve the sample quality, on effective and accurate storage/retrieval of samples for downstream processing, and on approaches to monitoring the quality of the library.

3:05 A Perspective and Prospective Assessment of High Throughput Analysis and Purification in Drug Discovery
Dr. Dan Kassel, Senior Director, Drug Discovery, Syrrx, Inc.
Fast turnaround times, minimal downtimes and high quality data underpin the mission/vision for most analytical groups supporting drug discovery. The vast majority of these discovery analytical groups have strived to provide high throughput analysis, purification, in vitro ADME and rapid PK bioanalysis. This presentation will take both a perspective and prospective look at the role of analytical chemistry and more particularly, LC/MS and LC/MS/MS in the drug discovery setting.

3:35 Refreshment Break

4:20 A Case for High-Throughput Supercritical Fluid Chromatography in Combinatorial Chemistry
Dr. Larry Truesdale, Director, Combinatorial Chemistry Technologies, Pfizer
The talk will focus on the benefits and utilization of SFC in high-throughput analysis and purification of combinatorial libraries for drug discovery. Comparisons to HPLC will be made.

4:50 Quality Assessment of Combinatorial Libraries and Screening Hits in a Single Experiment with a Multichannel Detection System
Dr. Ming-Shang Kuo, Senior Research Advisor, Discovery Technologies, and Dr. David A. Yurek, Senior Research Scientist, Discovery Technologies, Pharmacia Corporation
Despite the increasing levels of purification technology applied to the characterization of combinatorial libraries, it has often been shown that the libraries used for biological screening are less than desired. Along with identity and purity, the yield of the target compounds is a major concern. As the number of libraries produced increases, it is imperative to have a high-throughput means to characterize them. Currently, several assay systems are deployed to accomplish this, with MS used to identify the target compound. The yield and purity of the target compounds may be assessed by a number of means, with varying results. Obvious flaws exist in the use of MS, UV, and ELSD for these purposes. Recent introduction of a nitrogen detector compatible with HPLC solvents has provided a new means to assess yield. Together with a TOF-MS, it provides a synergistic effect enabling target and side-product structures to be identified and their concentrations and purities determined in a single experiment from a solution containing microgram levels of material. In this talk, we will discuss in detail of the technology development and its application in the area of high-throughput assessment of combichem libraries.

5:20 Panel Discussion

5:50 Close of Day 3

7:30am Light Continental Breakfast and Open Registration	Sponsored by:

8:20 Chairperson's Comments
Dr. C. Oliver Kappe, Karl-Franzens-University Graz

8:30 Keynote Presentation: Organic Synthesis Floating on Hot Water Dr. K. Barry Sharpless, The Scripps Research Institute Click reactions usually work best floating on water. Closed microwave reactors are ideal for this process at any desired temperature, allowing heating to at least 200°C.

9:00 Water and Ionic Liquids as Solvents and Reagents for Microwave-Assisted Synthesis
Dr. Nicholas Leadbeater, Department of Chemistry, King's College London
The use of water as a solvent for microwave-assisted metal-mediated catalysis will be discussed as will the use of ionic liquids as solvents and reagents for organic synthesis in conjunction with microwaves. The talk will show that these solvents offer many advantages over conventional organic media. The ability to control temperature and pressure very precisely using focused microwave systems has also allowed us to optimize conditions for conventional thermal reactions very rapidly and the results and implications of this will be discussed.

9:30 Aqueous Cyclodehydrations and Other Applications of Microwave-Assisted Synthesis in Parallel Medicinal Chemistry
Dr. Dean M. Wilson, Vertex Pharmaceuticals
In the quest for facile assembly of bioactive molecules, microwave-assisted synthesis has become a valuable tool for medicinal chemists. We have recently developed an aqueous cyclodehydration sequence to rapidly produce bicyclic pyrazoles, as well as other heterocycles. Additional results indicate powerful applicability of microwave synthesis to transformations useful for parallel medicinal chemistry, including heterocyclizations and cross coupling reactions.

10:00 The Use of Microwave Chemistry to Enable the Discovery of New Multicomponent Condensations
Dr. Mark Bradley, Professor of Combinatorial Chemistry and Director of the Combinatorial Centre of Excellence, University of Southampton
The use of microwave chemistry coupled with a variety of powerful analytical constructs to enable the discovery of new multicomponent condensations. This concept and the new reactions discovered to date will be presented.

10:30 Refreshment Break, Exhibit and Poster Viewing

11:00 Sponsored Presentation: Recent Advances in Microwave Synthesis Using Batch and Flow Reactors

Sponsored by:

Dr. Michael J. Collins, President and Chief Executive Officer, CEM Corporation Microwave synthesis has become a major new enabling technology for drug discovery and development. It has already gained widespread acceptance and use. This presentation will focus on some key new developments in the field that have dramatically enhanced the capabilities of microwave synthesis. Specific chemistries illustrating these enhancements will be presented. Also new technology for doing scale up and process development using microwaves will be presented. This technology is based on a new microwave flow reactor, which allows scale up from milligrams to kilograms. Simplified methodologies for translating batch reaction conditions to flow conditions will also be presented.

 

11:45 Sponsored Presentation: Practical Modern Approaches to Synthesis: Paving the Way for Groundbreaking Lead Development

Sponsored by:

Dr. Jon-Sverre Schanche, Chief Scientific Officer, Personal Chemistry AB · Dr. Jacob Westman, Director, Chemistry, Actar AB New and versatile approaches to synthesis of heterocycles, based upon novel intermediates, are giving rise to molecules of specific interest to medicinal chemistry. This approach, coupled with rapid synthesis, simplified work-up and scalability of the reactions, demonstrates the benefits of the Coherent Synthesis concept. Augmenting the technology with validated chemical approaches and knowledge management promises to transform the entire chemistry development process. Coherent Synthesis was first introduced in 1999 and has been readily adopted in many major pharmaceutical companies.

12:30 Luncheon (sponsored by Cambridge Healthtech Institute)

1:45 Sponsored Presentation: A Unique Multi-User Platform for Microwave Synthesis to Speed Drug Discovery

Sponsored by:

Dr. Ger Blok, Product Manager, Synthesis, Milestone Inc. The initial evaluation of microwave synthesis for medicinal chemistry has accelerated acceptance of the technology for early drug discovery. Now, the marketplace is rapidly moving towards reaction scale-up and process applications. This presentation will showcase how a single, multimode microwave labstation with interchangeable reactors can meet the varied sampling needs of research groups for single sampling or batch processing. Used by the top pharmaceutical laboratories around the world, this unique, multi-user platform offers unparalleled flexibility and ease-of use. Combinatorial chemistry, parallel synthesis, photochemistry, batch reactions, and scale-up will also be discussed, as will real world reaction examples.

2:30 High-Throughput Microwave-Accelerated Combinatorial Synthesis: A Plate-Based Approach
Dr. Christopher R. Sarko, Senior Principal Research Scientist, Boehringer-Ingelheim Pharmaceuticals Inc.
The advent of microwave-assisted synthesis has allowed chemists to rapidly optimize reaction conditions for combinatorial library development. However, a major issue with most commercially available microwave systems is the low throughput, typically 20 samples per hour. In an effort to increase throughput our group has developed a 96-well plate-based system for high-throughput microwave-assisted synthesis. This system is a closed-vessel system allowing reactions to be performed under significant pressures and temperatures. In this presentation we will overview the stages of development, lessons learned, and libraries produced for validation of this exciting new tool.

3:00 The Scale-up of Microwave-Assisted Organic Reactions
Dr. Alex Rabinovich, Senior Scientist, Combinatorial Chemistry Technologies, Pfizer
Microwave-assisted organic synthesis is a new and quickly developing area in synthetic organic chemistry. The scale-up process (up to 0.5 kg) of microwave-assisted organic reactions using Smith synthesizer (Personal Chemistry) and Ethos Microwave Labstation (Milestone) will be discussed.

3:30 Refreshment Break, Exhibit and Poster Viewing

3:50 Expeditious Synthetic Transformations Using Microwaves
Dr. Rajender S. Varma, Clean Processes Branch, National Risk Management Research Laboratory, U.S. Environmental Protection Agency
Microwave-expedited solvent-free synthetic processes will be described for the synthesis of a variety of industrially significant compounds and intermediates, namely, imines, enamines, nitroalkenes, enones, oxidized sulfur compounds, and ionic liquids. This solvent-free synthetic methodology involves microwave exposure of reactants in neat form or their reaction in presence of a catalyst or catalyzed by the surfaces of inexpensive and recyclable mineral oxides namely silica, alumina, clay, or "doped" surfaces. The salient features of these high yield protocols, namely the enhanced reaction rates, greater selectivity and the experimental ease of manipulation will be highlighted.

4:20 Keynote Presentation: Microwave-Assisted Heterocyclic Synthesis Dr. Alan R. Katritzky, Department of Chemistry, University of Florida Some of the results obtained and the potential for the application of microwaves for the synthesis for heterocycles would be discussed. In particular, their application to dipolar cycloaddition reactions and to substitution reactions of various types will be outlined.

5:00 Panel Discussion

5:30 Close of Conference

HOTEL INFORMATION
Hilton La Jolla Torrey Pines
10950 North Torrey Pines Road
La Jolla, CA 92037
T: 858-558-1500 • F: 858-450-4584
Cut-off Date: January 31, 2003
Room Rates: $199 S/D

Please call the hotel directly to make your room reservation. Identify yourself as a Cambridge Healthtech Institute conference attendee to receive the reduced room rate. Reservations made after the cut-off date or after the group room block has been filled (whichever comes first) will be accepted on a space-and-rate-availability basis. Rooms are limited, so please book early.

CALL FOR SPONSORS AND EXHIBITORS
Many sponsorship opportunities are available for your company to maximize its exposure and influence-including overall event and conference specific sponsorships, technology workshops, networking receptions, delegate bags, and badge lanyards. Over the course of the week, over 350 delegates will have access to the exhibit hall. The early rate for exhibit spaces is November 8, 2002. Exhibit registrations received by that date will save your company $300!

For more information on available sponsorship packages and exhibit space, please contact:
Angela Parsons at 781-972-5467 or aparsons@healthtech.com
or Deborah Brooks at 781-972-5412 or dbrooks@healthtech.com

CAR RENTAL INFORMATION
Special discount rentals have been established with AVIS for this conference. Please call AVIS directly at 800-331-1600 (you must reference our Avis Worldwide Discount Number J868190) or go to the following website www.avis.com/AvisWeb/html/meetings/webpage.html?1821

CALL FOR POSTERS
Cambridge Healthtech Institute encourages attendees to gain further exposure by presenting their work in the poster sessions. Please fill out the registration form, with the poster title and primary author. To ensure inclusion in the conference CD, a one-page abstract must be submitted and registration must be paid in full by January 24, 2003.   Click here for poster instructions

 

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