Real World Drug Discovery A Chemist's Guide to Biotech and Pharmaceutical Research

Transcription

1 Real World Drug Discovery A Chemist's Guide to Biotech and Pharmaceutical Research Robert M. Rydzewski ELSEVIER Amsterdam Boston Heidelberg London New York Oxford Paris San Diego San Francisco Singapore Sydney Tokyo

2 Preface Acknowledgements About the Author xii xvi xviii 1 The Drug Discovery Business to Date Introduction The Past Pharma Roots Biotech is Born The Genomics Revolution Current Economics Problems Cost of Drug Development The Productivity Gap Market Withdrawals Generic Competition Current Economics Solutions Pharma Profits and Market Expansion Mergers and Acquisitions Biotech Clinical Candidates to Pharma Academic Contributions Global Outsourcing Blockbusters and Orphan Drugs Repurposing Chiral Switching Combination Therapeutics Reformulation Summary 46

3 viii The Drug Discovery Business to Come 2.1 Introduction 2.2 New Models for Pharma R&D Minus R D Plus R Smaller is Better Specialty Drugs Pricing Pressures and Price Controls New Models for Academia and Biotech Translational Research The Standard Biotech Model "Is it a project or a company?" Leaner, Meaner Start-ups Biotech Alternatives New Technologies S-Curves and Expectations Genomics Redux Personalized Medicine Pharmacogenomics Other "Omics" The Adoption of Personalized Medicine Summary Industrial Considerations Intellectual Property The Value of New Ideas Patents Outside Resources Consultants Academic or Government Research Agreements Big Company-Small Company Collaborations The New Drug R&D Process Target Identification Lead Identification Lead Optimization Preclinical Stages in Clinical Development What are the Odds? How Things Get Done: The Project Team Introduction The Project Team The Project Goal Project Team Organization Project Team Meetings 164

4 jx 4.3 Conclusions Summing Up Is it Really Best? The Benefits Project Considerations Introduction Established Targets Established "Tough Targets" Novel Targets Identifying New Targets Target Validation Working on Novel Target-Directed Projects Targets Arising from Phenotype or High-Content Screening Phenotype Screening Versus Target Screening Elucidation of Phenotype-Derived Targets In Conclusion Hit Generation Introduction Definitions Groups Involved in Hit-to-Lead High-Throughput Screening History Myths and Truths about HTS Approaches to Hit Generation Random or Non-Directed Methods Screening of Synthetic Compound Collections Screening of Combinatorial Diversity Libraries Fragment Screening Screening of Natural Products and DOS Libraries Directed or Knowledge-Based Methods Turning Hits into Drugs What Now? Biochemical Mechanism in Hit Selection Competition and Allostery Irreversibility Slow Off-Rate Compounds Why Mechanism Matters Druglikeness What is It? Predicting Druglikeness Multidimensional Optimization 293

5 7.5 Lead Optimization Versus HTL Using Structure-Based Drug Design Definition, History, and Goals Potential Limitations Examples Working with Modelers Conclusions 308 Initial Properties Why Not All At Once? Potency What, Why, and How Much? Species Specificity Selectivity Selectivity... Not! Antitargets Structural Novelty Bioisosteres, Group, and Atom Replacements Scaffold Hopping, Morphing, and Grafting Cyclization and Ring Opening Other Methods Solubility Defining, Estimating, and Measuring Solubility Problems Resulting from Poor Solubility Improving Solubility Chemical and Plasma Stability Definitions and Importance Common Types of Instability 341 ADME and PK Properties Cell Permeability and Absorption Definitions A Closer Look at Intestinal Absorption Models of Cell Permeability and Absorption Improving Cell Permeability and Absorption Metabolic Stability Common Metabolic Transformations Assessing Metabolic Stability Improving Metabolic Stability Plasma Protein Binding Is It Important? Measuring Plasma Protein Binding Minimizing Plasma Protein Binding 398

6 xi 9.4 P-Glycoprotein Interactions Structure and Function Types of P-gp Interactions Measuring P-gp Interactions Reducing P-gp Interactions Bioavailability Introduction Understanding and Overcoming Poor Oral Bioavailability Things to Keep in Mind Toxicity-Related Properties CYP Inhibition Importance Types of CYP Inhibition CYP Inhibition Assays Common Structural Features of CYP Inhibitors Ways to Reduce CYP Inhibition CYP Induction Binding to the herg receptor Introduction In Vitro Assays Models of herg binding Reducing herg Interactions Mutagenicity Background Structural Aspects A Career in Drug Discovery Research Hiring: A Good Match What Do Employers Want? What Should a Candidate Look For? Assessing Performance Evaluations Promotions The Long Haul: Perspectives Job and Industry Evolution The Evolution of a Research Career Frustration Hope 490 Appendix Best-Selling Small Molecule Single Agent Prescription Drugs: "The Periodic Table of Drugs 2006" 495 Index 499