Basic Principles of Drug Discovery and Development

Blass, Benjamin E.As an industrial medicinal chemist, Dr. Blass has experience with major pharmaceutical organizations (Wyeth, Procter & Gamble Pharmaceuticals) and small biotech operations (Fox Chase Chemical Diversity Center), which provided him with a wealth of expertise in the art of drug discovery and development (including a wide range of disease states and biological targets). His position with Temple University's School of Pharmacy and the Moulder Center for Drug Discovery has provided him with essential experience as an educator and academic scientist. These experiences, as well as his training and expertise as a registered US patent agent, have provided him with the tools and skills necessary to bridge the gap between industrial drug discovery and academic research.

Basic Principles of Drug Discovery and Development presents the multifaceted process of identifying a new drug in the modern era, providing comprehensive explanations of enabling technologies such as high throughput screening, structure based drug design, molecular modeling, pharmaceutical profiling, and translational medicine, all areas that have become critical steps in the successful development of marketable therapeutics.

The text introduces the fundamental principles of drug discovery and development, also discussing important drug targets by class, in vitro screening methods, medicinal chemistry strategies in drug design, principles in pharmacokinetics and pharmacodynamics, animal models of disease states, clinical trial basics, and selected business aspects of the drug discovery process. It is designed to enable new scientists to rapidly understand the key fundamentals of drug discovery, including pharmacokinetics, toxicology, and intellectual property."

• Provides a clear explanation of how the pharmaceutical industry works
• Explains the complete drug discovery process, from obtaining a lead, to testing the bioactivity, to producing the drug, and protecting the intellectual propertyIdeal for anyone interested in learning about the drug discovery process and those contemplating careers in the industry
• Explains the transition process from academia or other industries

Foreword
1. Drug Discovery and Development: An Overview of Modern Methods and Principles
Drug Discovery and Development from 20,000 Feet
Target Selection: The First Step Forward
Hit Identification: Finding a Starting Point
Identify a Clinical Candidate: Juggling the Properties
Questions
References
2. The Drug Discovery Process: From Ancient Times to the Present Day
The Age of Botanicals: Preindustrial Drug Discovery
Paul Ehrlich: The Father of Modern Drug Discovery
Milestones in Drug Discovery
Milestones in Animal Models: Breeding a Better Model
Milestones in Molecular Science
X-ray Crystallography
Molecular Modeling and Computational Chemistry
High Throughput Technology: Chemical Synthesis and Screening Science
Milestones in Biotechnology
Recombinant DNA and Transfection Technology
Polymerase Chain Reaction (PCR) Technology
Monoclonal Antibody and Hybridoma Technology
The Rise of Biologics and Macromolecular Therapeutics
Societal and Governmental Impacts
The Pure Food and Drug Act of 1906
The Elixir of Sulfanilamide Disaster of 1937
The Thalidomide Story
Regulatory Milestones
Durham-Humphrey Amendment of 1951
Kefauver-Harris Amendment of 1962
Hatch-Waxman Act of 1984
Biologics Price Competition and Innovation Act of 2009
Future Developments in Drug Discovery
Questions
References
3. Classical Targets in Drug Discovery
Protein Structure
Enzymes
Inhibition of Enzymes
G-Protein-Coupled Receptors (GPCRs)
G-Protein-Dependent Signaling pathways
cAMP Signaling
IP₃ Signaling
Modulating GPCR Activity
Ion Channels
Gating Mechanisms
Ligand-Gated Channels
Voltage-Gated Channels
Other Gating Mechanisms
Membrane Transport Proteins (Transporters)
Emerging Targets
Questions
References
4. In Vitro Screening Systems
The Language of Screening: Basic Terms
Concentration Response Curves and IC50s
Dissociation Constants (K_d) and Inhibition Constants (K_i)
Efficacy versus Binding: EC_50s
Agonist, Partial Agonist, Antagonist, Allosteric Modulators, and Inverse Agonists
Agonists and Partial Agonists
Antagonists
Basal Activity and Inverse Agonists
Allosteric Modulation
Receptor Reserve
Streptavidin and Biotin
Biochemical versus Cellular Assays
Assay Systems and Methods of Detection
Radioligand Systems
Scintillation Proximity Assay (SPA)
Enzyme-Linked Immunosorbent Assay (ELISA)
Fluorescence-Based Assay Systems
Fluorescence Polarization (FP)
Fluorescence Resonance Energy Transfer (FRET)
Time-Resolved Fluorescence Resonance Energy Transfer (TRFRET)
Amplified Luminescent Proximity Homogeneous Assay (AlphaScreenT)
Fluorescent Detection of Calcium Flux
Reporter Gene Assays
Chloramphenicol Acetyltransferase (CAT)
ß-Lactamase Reporter Assays
Luciferase Reporter Assays
Kinetic Fluorescent Measurement Systems
Label-Free Assay Systems
Cellular Dielectric Spectroscopy
Optical Biosensors
Surface Plasmon Resonance Technology
Electrophysiological Patch Clamp
General Consideration for All Screening Methods
Questions
References
5. Medicinal Chemistry
Structure-Activity Relationships and Structure-Property Relationships
The Role of Chirality
Push and Pull in Structure-Activity Relationships
Quantitative Structure-Activity Relationships
The Pharmacophore
Developing an SAR Data Set
The Structure-Activity Relationship Cycle
Bioisosterism
Structure-Activity Relationship, Selectivity and Physicochemical Properties
"Druglike” Guidelines
Questions
References
6. In vitro ADME and In vivo Pharmacokinetics
Absorption
Solubility
Permeability
Distribution
Permeability
Transporters
Plasma Protein Binding
Elimination Pathways
Metabolism
Excretion
In vitro ADME Screening Methods
In Vivo Pharmacokinetics
Volume of Distribution
Clearance
Half-life
Bioavailability
Species selection
Questions
References
7. Animal Models of Disease States
Sources of Animal Models
Validity of Animal Models
Species Selection
Number of Animals
Exemplary Animal Models by Disease Category
Animal Models in Neuroscience
Animal Models of Neurodegeneration
Animal Models of Cardiovascular Disease
Models of Hypertension
Models of Hyperlipidemia and High Cholesterol
Models of Atrial Fibrillation
Models of Heart Failure
Animal Models of Infectious Disease
Murine Thigh Infection Model
Murine Model of Systemic Infection
The Mouse Model of Influenza Virus Infection
Limitations of Animal Models of Infection
Animal Models of Oncology
Mouse Xenograft Tumor Model
Mouse Allograft Tumor Model
Genetically Engineered Mouse Models of Cancer
Questions
References
8. Safety and Toxicology
Sources of Toxicity
Acute versus Chronic Toxicity
Cytotoxicity
Carcinogenicity, Genotoxicity, and Mutagenicity
Drug-Drug Interactions
Cardiovascular Safety and Toxicology Studies
Central Nervous System Safety and Toxicology Studies
Immune System Mediated Safety Issues
Teratogenicity
In Vivo Toxicity and Safety Studies
Questions
References
9. Basics of Clinical Trials
Before the Clinic
Drug Supply
Delivery Methods
Formulation
Investigational New Drug Application
Phase I Clinical Trials
Phase II Clinical Trials
Phase III Clinical Trials
Phase IV Clinical Trials
Adaptive Clinical Trial Design
Questions
References
10. Translational Medicine and Biomarkers
Definition of a Biomarker and Their Classification
Characteristics and Impact of Biomarkers
Biomarkers versus Surrogate End Points
Imaging Technologies
The Practical Application of Biomarkers
DPP-IV Inhibitors (Januvia®)
Physiological Measurements as Biomarkers: Orexin Antagonists
FDG PET Imaging Agent
The Neurokinin 1 (NK₁) Receptor, Depression, and PET Imaging: The Aprepitant Story
Questions
References
11. Organizational Considerations and Trends in the Pharmaceutical Industry
Organizational Structures of Pharmaceutical Companies
Business Divisions Interactions
The Discovery Project Team Evolutionary Cycle
The Business Climate
Mergers and Acquisitions
Contract Research Organizations
Academic Drug Discovery
Funding Issues
Questions
References
12. Intellectual Property and Patents in Drug Discovery
Patentable Subject Matter
Inherent Properties and Patentability
Novelty and the Prior Art
Obviousness and the Prior Art
Inventorship
Assignment and Ownership
Classification of Patents and Patent Applications
Impact of Overlapping Patents
Patent Applications and their Contents
Contents of a Patent Application
Questions
References
13. Case Studies in Drug Discovery
Tamiflu: From Mechanism of Action to Marketed Drug
Histone Deacylase Inhibitors: Physicochemical Optimization via Structural Change
HIV Protease Inhibitors: Chemically Complex Miracle Drugs
Nitrofurantoin: A Surprisingly Successful Drug
Seldane® (Terfenadine) versus Allegra® (Fexofenadine): Metabolism Matters: Safety
Claritin® (Loratadine) versus Clarinex® (Desloratadine): Metabolism Matters: Pharmacokinetics
MPTP: Parkinson's Disease in a Bottle
Bupropion and Methylphenidate: Improving Performance via Formulation Changes
Selective Inhibition of Cyclooxygenase-2: The Impact of an Inadequate Written Description
Questions
References
Answers to Questions in Textbook by Chapter
Subject Index
Drug Index