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A thorough analysis of recent trends in medicinal chemistry and evaluation of their significance for ad-vancing productivity in drug discovery is presented. This report includes:

• A critical evaluation of chemical and computational technological modalities, their current and potential value, and their commercial manifestations.

• A consideration of market dynamics with an emphasis on outsourcing and user views on the implications of current practices in drug discovery organizations.

• Insights gleaned from an ex-tensive literature review, discus-sions with industry experts, and an opinion survey of personnel active in medicinal chemistry for drug discovery.

Impact of medicinal

chemistry trends on R&D

productivity

Medicinal Chemistry for

Significance of Recent Trends Ken Rubenstein, PhD

Drug Discovery

March 2009

overview

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tables and Figures

FiguresThe Molecular Diversity SpectrumPXR—Promiscuous Ligand-Binding Site tablesExamples of Drug Targets for which High-Resolution X-ray

Structures are AvailableTechnological Approaches of Selected Drug Discovery

Outsourcing VendorsProduct/Service Offerings of Selected Drug Discovery

Outsourcing Vendors

Compounds Derived from Fragment-Based Drug Design Currently in Clinical Trials

Selected Outsourcing Deals survey tablesSurvey Respondents by Job PositionSurvey Respondents by Job FunctionInvolvement in Drug Discovery ChemistryStages of Chemistry Respondents are Involved InCurrent and Projected Involvement in Structure-Based

Drug Design

table 3.4. Representative next-Generation sequencing Companies

Medicinal Chemistry for Drug Discovery: Significance of Recent Trends reviews the state of the art and aims to de-termine the significance of technology and market trends in me-dicinal chemistry for advancing productivity in drug discovery. Although the fundamental task of medicinal chemists has not changed drastically over time, the chemical and computational tools and perspectives at their disposal have advanced signifi-cantly. One in particular, fragment-based drug design, stands out as promising major improvements in research productivity.

We examine medicinal chemistry-related approaches and methodologies that drug discovery organizations employ in an effort to increase productivity in early drug discovery and decrease attrition at later pipeline stages. Key topics consid-ered include structure-based drug design, fragment-based drug design, natural products-based drug design, diversity-oriented synthesis, and chemogenomics. An overall assessment of the current and potential value of these approaches is presented. Various flavors of com-puter-aided drug design are also considered, as the complexity and limi-tations of drug discovery programs that are based on biochemical screens of large compound col-lections have been major factors in stimulating the growth of this modality.

Each of the aforemen-tioned technological mo-dalities is viewed in terms of practical examples and commercial activity. Out-

sourcing arises as a prominent theme in the applications realm, with special emphasis on companies with primary operations in countries with developing economies, notably China, India, and Russia. Among 32 companies considered, structure-based drug design is the most prevalent activity with most players emphasizing the fragment-based variation. Virtual screening is the second-most prevalent modality, whereas natural prod-ucts, diversity-oriented synthesis, and chemogenomics appear in only a small minority of cases.

Outsourcing vendors are viewed according to participation in hit discovery, hit-to-lead synthesis, lead optimization, library synthesis, in-house drug discovery, and virtual drug design. More than one-third of the companies considered have opera-tions primarily located in countries with emerging economies. A large majority of companies offer computer-based services, hit-to-lead, lead optimization, and library synthesis. Fewer engage in hit discovery, and a small minority do their own

drug discovery.

Medicinal Chemistry for Drug Discovery: Significance of Recent Trends next examines deal activity and the influence of outsourcing on research productivity. Results from a survey of managers and researchers active in the field provide a multifaceted picture of practices and attitudes prevalent in drug discovery organizations today. Con-clusions from the user survey highlight which modalities are viewed as having greater potential to make an impact on productivity. Finally, the complete tran-scripts of seven interviews with experts in the field are provided.

About the Author: Ken Rubenstein, PhD, a biochemist and molecular biologist, received his PhD at the University of Wisconsin and postdoctoral training at the University of Pennsylvania School of Medicine. He was a key innovator and research manager for Syva Company, the diagnostics branch of Syntex Corporation. During his 13 years with Syva, Dr. Rubenstein became vice president, scientific affairs, a function that included strategic planning. Since 1983, he has served as a technology and marketing consultant to biomedical companies and an industry analyst, with more than 40 published studies to his credit.

Source: Insight Pharma Reports

Chapter 1: Introduction1.1. Background1.2. Scope and Nature of the Report

Chapter 2: Evolution of organic and medicinal Chemistry in Pharma2.1. Pharmaceutical Trends over Time2.2. Combinatorial Chemistry2.3. Lipinski’s Rule of Five2.4. Impact of Lipinski’s Rule of Five

Chapter 3: organic and medicinal Chemistry technologies for drug discovery3.1. Computer-Aided Drug DesignVirtual ScreeningTarget Structure-Based DesignLigand Structure-Based DesignDe Novo Compound DesignQSAR (Quantitative Structure-Activity Relationship)Fragment-Based Drug Design3.2. Diversity-Oriented Synthesis in Drug Design3.3. Natural Products-Based Drug Design3.4. Chemogenomics and Drug Design3.5. Perspectives

Chapter 4: Applications of organic and medicinal Chemistry in drug discovery4.1. Overview of Technology Approaches of Outsourcing

Vendors4.2. Overview of Service Offerings by Drug Discovery

Outsourcing Vendors4.3. Structure-Based Drug Design4.4. Fragment-Based Drug Design

4.5. Natural Products-Based Drug Discovery4.6. Diversity-Oriented Synthesis in Drug Discovery4.7. Virtual Screening

Chapter 5: market dynamics5.1. Outsourcing Dynamics5.2. Survey of Chemists and Managers Active in Medicinal

ChemistrySurvey Conclusions

Chapter 6: Conclusions and Future trends6.1. Optimizing the Interplay of Chemistry and Biology6.2. Marrying the “Industrialization” of Drug Discovery

with Intellectual Process

Chapter 7: Expert Interviews7.1. Christopher Lipinski, PhD, Drug Discovery Consultant;

Retired Senior Research Fellow, Pfizer7.2. Celerino Abad-Zapatero, PhD, Adjunct Professor,

University of Illinois at Chicago, Center for Pharmaceutical Biotechnology

7.3. Medicinal Chemistry Executive Anonymous, Veteran from Big Pharma

7.4. Gilbert Rishton, PhD, Founder & Director, Alzheimer’s Institute, California State University Channel Islands

7.5. Steven Muskal, PhD, CEO, Eidogen-Sertanty7.6. Informatics Chemist, Anonymous, Big Pharma7.7. Sidney Topiol, PhD, Associate Director, Computational

Chemistry, Lundbeck Research

References

Company Index with Web Addresses

table of Contents

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Current and Projected Involvement in Ligand-Based Drug Design

Current and Projected Involvement in Quantitative Structure-Activity Relationship

Current and Projected Involvement in Fragment-Based Drug Design

Current and Projected Involvement in Natural Products-Based Drug Design

Current and Projected Involvement in Diversity-Oriented Synthesis for Drug Design

Current and Projected Involvement in ChemogenomicsSignificance of Approaches for Advancing ProductivityUse of Virtual Screening in Selection of Screening LibrariesEffect of Structure/Fragment-Based Design on Preclinical

Success

Effect of Structure/Fragment-Based Design on Phase II Success

Extent of Natural Products InclusionInfluence of Natural Product Structures on Library DesignMakeup of Libraries Selected for Primary ScreensContribution of Computer-Aided Drug DesignOutsourcing Synthesis for Primary Screening LibrariesOutsourcing Synthesis of Hit-to-Lead LibrariesOutsourcing Synthesis for Lead OptimizationOutsourcing Synthesis for Process DevelopmentOrganic/Medicinal Chemistry Budget Expectations, 2009Organic/Medicinal Chemistry Budget Expectations,

3-Year Projection

tables and Figures (cont.)

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CHI Insight Pharma Reports are written by experts who collabo-rate with CHI to provide a series of reports that evaluate the salient trends in pharmaceutical technology, business, and therapy markets. Insight Pharma Reports are used by senior decision makers at life science companies to keep abreast of the latest advances in pharmaceutical R&D, their potential applications and business im-pacts. Our clients include the top 50 pharmaceutical companies, top 100 biotechnology companies, and top 100 vendors of life science products and services. Typical purchasers are managers, directors, and VPs in business development, discovery research, clinical develop-ment, strategic planning, portfolio management, new product planning, and marketing.Insight Pharma Reports offer:

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