Real World Drug Discovery

Real World Drug Discovery

A Chemist's Guide to Biotech and Pharmaceutical Research

1st Edition - September 10, 2008

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  • Authors: Robert Rydzewski, Robert Rydzewski
  • eBook ISBN: 9780080914886

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Description

Drug discovery increasingly requires a common understanding by researchers of the many and diverse factors that go into the making of new medicines. The scientist entering the field will immediately face important issues for which his education may not have prepared him: project teams, patent law, consultants, target product profiles, industry trends, Gantt charts, target validation, pharmacokinetics, proteomics, phenotype assays, biomarkers, and many other unfamiliar topics for which a basic understanding must somehow be obtained. Even the more experienced scientist can find it frustratingly difficult to get an overview of the many factors involved in modern drug discovery and often only after years of exploring does a whole and integrated picture emerge in the mind of the researcher.Real World Drug Discovery: A Chemist’s Guide to Biotech and Pharmaceutical Research presents this kind of map of the landscape of drug discovery. In a single, readable volume it outlines processes and explains essential concepts and terms for the recent science graduate wondering what to expect in pharma or biotech, the medicinal chemist seeking a broader and more timely understanding of the industry, or the contractor or collaborator whose understanding of the commercial drug discovery process could increase the value of his contribution to it.

Key Features

  • Interviews with well-known experts in many of the fields involved, giving insightful comments from authorities on many of the sub-disciplines important to cutting edge drug discovery.
  • Helpful suggestions gleaned from years of experience in biotech and pharma, which represents a repository drug discovery "lore" not previously available in any book.
  • "Periodic Table of Drugs" listing current top-selling drugs arranged by target and laid out so that structural similarities and differences are plain and clear.
  • Extensive use of diagrams to illustrate concepts like biotech startup models, preteomic profiling for target identification, Gantt charts for project planning, etc.

Readership

Graduate students and others moving into medicinal chemistry/pharma research, current drug discovery researchers, academic collaborators, and contract researchers.

Table of Contents

  • Chapter 1 – The Drug Discovery Business to Date
    I. Introduction
    II. The Past
    A. Pharma Roots
    B. Biotech is Born
    C. The Genomics Revolution
    III. Current Economics—Problems
    A. Cost of Drug Development
    B. The Productivity Gap
    C. Market Withdrawals
    D. Generic Competition
    IV. Current Economics—Solutions
    A. Pharma Profits and Market Expansion
    B. Mergers and Acquisitions
    C. Biotech Clinical Candidates to Pharma
    D. Academic Contributions
    E. Global Outsourcing
    F. Blockbusters and Orphan Drugs
    G. Repurposing
    H. Chiral Switching
    I. Combination Therapeutics
    J. Reformulation
    V. Summary
    References

    Chapter 2 – The Drug Discovery Business to Come
    I. Introduction
    II. New Models for Pharma
    A. R&D Minus R
    B. D Plus R
    C. Smaller is Better
    D. Specialty Drugs
    E. Pricing Pressures and Price Controls
    III. New Models for Academia and Biotech …
    A. Translational Research
    B. The Standard Biotech Model
    C. “Is it a project or a company?”
    D. Leaner, Meaner Startups
    E. Biotech Alternatives
    IV. New Technologies
    A. S-Curves and Expectations
    B. Genomics Redux
    C. Personalized Medicine
    D. Pharmacogenomics
    E. Other “Omics”
    F. The Adoption of Personalized Medicine
    V. Summary
    References

    Chapter 3 – Industrial Considerations
    I. Intellectual Property .. 1
    A. The Value of New Ideas
    1. Invention Disclosures
    2. Notebooks and Data Recording
    3. Avoiding Inappropriate Disclosure
    B. Patents
    1. Introduction and Definition
    2. Patent Requirements
    a. Novelty, Priority, and Prior Art
    b. Unobviousness
    c. Utility
    3. Reading and Searching Patents
    a. Some Preliminaries
    b. Patent Anatomy
    c. Locating Information in Patents
    4. Inventorship
    II. Outside Resources
    A. Consultants
    B. Academic or Government Research Agreements
    C. Big Company-Small Company Collaborations
    III. The New Drug R&D Process
    A. Target Identification
    B. Lead Identification
    C. Lead Optimization
    D. Preclinical
    E. Stages in Clinical Development
    F. What Are the Odds?
    References

    Chapter 4 – How Things Get Done: The Project Team
    I. Introduction
    II. The Project Team
    A. The Project Goal
    1. Compound Validation Goals
    2. Target Validation Goals
    B. Project Team Organization
    1. The Matrix Management System
    a. Day-to-Day Supervision
    b. Target Compounds
    c. Progress Reporting
    d. Performance Evaluations
    2. Project Team Roles
    a. Project Team Leader
    b. Project Team Member
    c. Project Team Representative
    d. Project Team Manager
    C. Project Team Meetings
    1. Meeting Scheduling
    2. The Meeting Agenda
    3. Meeting Notes
    4. Action Items
    5. Project Planning Tools
    III. Conclusions
    A. Summing Up
    B. Is It Really Best?
    C. The Benefits
    References

    Chapter 5 – Project Considerations
    I. Introduction
    II. Established Targets
    III. Established “Tough Targets”
    IV. Novel Targets
    A. Identifying New Targets
    B. Target Validation
    1. Levels of Validation
    2. Target Validation Tools
    a. Knockouts and Knock-Ins
    b. Antisense Oligonucleotides
    c. RNAi
    d. Antibodies
    e. Aptamers
    f. Small Molecules
    C. Working on Novel Target-directed Projects
    V. Targets Arising from Phenotype or High-Content Screening
    A. Phenotype Screening Versus Target Screening
    B. Elucidation of Phenotype Targets
    VI. In Conclusion
    References

    Chapter 6 – Hit Generation
    I. Introduction
    II. Definitions
    III. Groups Involved
    IV. High-Throughput Screening
    A. History
    B. Myths and Truths about HTS
    V. Approaches to Hit Generation
    A. Random or Non-directed Methods
    B. Screening of Synthetic Compound Collections
    C. Screening of Combinatorial Diversity Libraries
    D. Fragment Screening
    1. Detecting Fragment Binding
    2. Optimizing Fragment Hits
    E. Screening of Natural Products and DOS Libraries
    F. Directed or Knowledge-based Methods
    1. Methods Based on Endogenous Ligands or Substrates
    2. Methods Based on Other Leads
    G. Computational Methods
    References

    Chapter 7 – Turning Hits into Drugs
    I. What Now?
    II. Biochemical Mechanisms in Hit Selection
    A. Competition and Allostery
    B. Irreversibility
    C. Slow Off-rate Compounds
    D. Why Mechanism Matters
    III. Druglikeness
    A. What Is It?
    B. Predicting Drug-likeness
    IV. Multidimensional Optimization
    V. Lead Optimization Versus HTL
    VI. Using Structure-Based Drug Design
    A. Definition, History, and Goals
    B. Potential Limitations
    1. Conformational Flexibility
    2. Other Limitations
    C. Examples
    1. HIV Protease Inhibitors
    2. Other Examples
    D. Working with Modelers
    E. Conclusions
    References

    Chapter 8 – Initial Properties
    I. Why Not All At Once?
    II. Potency
    A. What, Why, and How Much?
    B. Species Specificity
    III. Selectivity
    A. Selectivity … Not!
    B. Antitargets
    IV. Structural Novelty
    A. Bioisosteres, Group, and Atom Replacements
    1. Definition and Utility
    2. Examples
    B. Scaffold Hopping, Morphing, and Grafting
    C. Cyclization and Ring Opening
    D. Other Methods
    V. Solubility
    A. Defining, Estimating, and Measuring Solubility
    B. Problems Resulting from Poor Solubility
    C. Improving Solubility
    1. Molecular Modifications
    2. Prodrugs
    VI. Chemical and Plasma Stability
    A. Definitions and Importance
    B. Common Types of Instability
    1. Oxidative Instability
    2. Chiral Instability
    3. Hydrolytic Instability
    References

    Chapter 9 – ADME and PK Properties
    I. Cell Permeability and Absorption
    A. Definitions
    B. A Closer Look at Intestinal Absorption
    C. Models of Cell Permeability and Absorption
    1. Property-based Predictions
    2. Immobilized Artificial Membranes
    3. PAMPA
    4. Caco-2 and Other Monolayer Assays
    D. Improving Cell Permeability and Absorption
    1. Molecular Modifications
    2. Prodrugs
    II. Metabolic Stability
    A. Common Metabolic Transformation
    1. Hydrolysis of Esters and Amides
    2. Oxidations of Arenes, Alkenes, and Alkynes
    3. Aliphatic Hydroxylation
    4. Oxidations at or Adjacent to Heteroatoms
    5. Glucuronidation
    6. Overview
    B. Assessing Metabolic Stability
    1. Recombinant DMEs
    2. Liver Microsomes
    3. Liver Cytosol and S9
    4. Hepatocytes
    C. Improving Metabolic Stability
    1. Metabolite Identification
    2. Caveats
    3. Structural Modifications
    III. Plasma Protein Binding
    A. Is It Important?
    B. Measuring Plasma Protein Binding
    C. Minimizing Plasma Protein Binding
    IV. P-glycoprotein Interactions
    A. Structure and Function
    B. Types of P-gp Interactions
    C. Measuring P-gp Interactions
    D. Reducing P-gp Interactions

    Chapter 10 – Toxicity-Related Properties
    I. CYP Inhibition
    A. Importance
    B. Types of CYP Inhibition
    C. CYP Inhibition Assays
    D. Common Structural Features
    E. Ways to Reduce CYP Inhibition
    1. Reduce Lipophilicity
    2. Remove or Replace Offending Features
    3. Sterically Hinder Coordinating Nitrogens
    4. Find a Way to “Insult” the CYP
    II. CYP Induction
    III. HERG Binding
    A. Introduction
    B. In Vitro Assays
    C. Models of hERG Binding
    D. Reducing hERG Interactions
    IV. Mutagenicity
    A. Background
    B. Structural Aspects
    References

    Chapter 11 – A Career in Drug Discovery
    I. Hiring: A Good Match
    A. What Do Employers Want?
    1. The Candidate Selection Process
    a. The Resume
    b. Recommendations
    c. The Interview
    2. Selection Criteria
    B. What Should a Candidate Look For?
    1. The Company
    2. Compensation and Benefits
    3. Some Questions To Ask
    II. Assessing Performance
    A. Evaluations
    B. Promotions
    III. The Long Haul: Perspectives
    A. Job and Industry Evolution
    B. The Evolution of a Research Career
    C. Frustration
    D. Hope
    References

Product details

  • No. of pages: 600
  • Language: English
  • Copyright: © Elsevier Science 2008
  • Published: September 10, 2008
  • Imprint: Elsevier Science
  • eBook ISBN: 9780080914886

About the Authors

Robert Rydzewski

Over 24 years experience in industry including positions at: Celera Genomics, Gensia Pharmaceuticals, Syntex Corporation, Shell Development and G.D. Searle and Company.

Author of 21 papers, 12 patent applications and 2 book chapters.

Affiliations and Expertise

Newark, CA, USA

Robert Rydzewski

Over 24 years experience in industry including positions at: Celera Genomics, Gensia Pharmaceuticals, Syntex Corporation, Shell Development and G.D. Searle and Company.

Author of 21 papers, 12 patent applications and 2 book chapters.

Affiliations and Expertise

Newark, CA, USA

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