Drug Like Properties 2nd Edition by Li Di, Edward H Kerns ISBN 0128013229 9780128013229

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ISBN 10: 0128013229
ISBN 13: 9780128013229
Author: Li Di, Edward H Kerns

Of the thousands of novel compounds that a drug discovery project team invents and that bind to the therapeutic target, only a fraction have sufficient ADME (absorption, distribution, metabolism, elimination) properties, and acceptable toxicology properties, to become a drug product that will successfully complete human Phase I clinical trials. Drug-Like Properties: Concepts, Structure Design and Methods from ADME to Toxicity Optimization, Second Edition, provides scientists and students the background and tools to understand, discover, and develop optimal clinical candidates. This valuable resource explores physiochemical properties, including solubility and permeability, before exploring how compounds are absorbed, distributed, and metabolized safely and stably. Review chapters provide context and underscore the importance of key concepts such as pharmacokinetics, toxicity, the blood-brain barrier, diagnosing drug limitations, prodrugs, and formulation. Building on those foundations, this thoroughly updated revision covers a wide variety of current methods for the screening (high throughput), diagnosis (medium throughput) and in-depth (low throughput) analysis of drug properties for process and product improvement. From conducting key assays for interpretation and structural analysis, the reader learns to implement modification methods and improve each ADME property.

Through valuable case studies, structure-property relationship descriptions, and structure modification strategies, Drug-Like Properties, Second Edition, offers tools and methods for ADME/Tox scientists through all aspects of drug research, discovery, design, development, and optimization.

Drug Like Properties 2nd Table of contents:

Preface

• Preface to Second Edition
• Preface to First Edition

Chapter 1: Introduction

• Abstract
• 1.1 Drug-like Properties in Drug Discovery
• 1.2 Purpose of This Book
• Problems

Chapter 2: Benefits of Property Assessment and Good Drug-Like Properties

• Abstract
• 2.1 Introduction
• 2.2 Discovery Scientists Optimize Many Properties
• 2.3 Introduction to the Drug Discovery and Development Process
• 2.4 Benefits of Good Drug-like Properties
• 2.5 Property Profiling in Drug Discovery
• 2.6 Drug-like Property Optimization in Drug Discovery
• Problems

Chapter 3: In Vivo Environments Affect Drug Exposure

• Abstract
• 3.1 Introduction
• 3.2 Drug Dosing
• 3.3 Stomach
• 3.4 Intestinal Environment
• 3.5 Bloodstream
• 3.6 Liver
• 3.7 Kidney
• 3.8 Blood-Tissue Barriers
• 3.9 Tissue Distribution
• 3.10 Consequences of Chirality
• 3.11 Overview of in vivo Challenges to Drug Exposure
• Problems

Chapter 4: Prediction Rules for Rapid Property Profiling from Structure

• Abstract
• 4.1 Introduction
• 4.2 General Concepts for Prediction Rules
• 4.3 Rule of 5
• 4.4 Veber Rules
• 4.5 Waring Rules
• 4.6 Golden Triangle
• 4.7 Other Predictive Rules
• 4.8 Application of Rules for Compound Assessment
• 4.9 Applications of Predictive Rules
• Problems

Chapter 5: Lipophilicity

• Abstract
• 5.1 Lipophilicity Fundamentals
• 5.2 Lipophilicity Effects
• 5.3 Lipophilicity Case Studies and Structure Modification
• Problems

Chapter 6: pK_a

• Abstract
• 6.1 pK_a Fundamentals
• 6.2 pK_a Effects
• 6.3 pK_a Case Studies
• 6.4 Structure Modification Strategies for pK_a
• Problems

Chapter 7: Solubility

• Abstract
• 7.1 Introduction
• 7.2 Solubility Fundamentals
• 7.3 Effects of Solubility
• 7.4 Effects of Physiology on Solubility and Absorption
• 7.5 Structure Modification Strategies to Improve Solubility
• 7.6 Strategies to Improve Dissolution Rate
• 7.7 Salt Form
• 7.8 Strategy for Solubility During Drug Discovery
• Problems

Chapter 8: Permeability

• Abstract
• 8.1 Introduction
• 8.2 Permeability Fundamentals
• 8.3 Permeability Effects
• 8.4 Permeability Structure Modification Strategies
• 8.5 Strategy for Permeability
• Problems

Chapter 9: Transporters

• Abstract
• 9.1 Introduction
• 9.2 Transporter Fundamentals
• 9.3 Transporter Effects
• 9.4 Efflux Transporters
• 9.5 Uptake Transporters
• Problems

Chapter 10: Blood-Brain Barrier

• Abstract
• 10.1 Introduction
• 10.2 Fundamentals of Brain Exposure
• 10.3 Effects of Brain Exposure on Efficacy and Drug Development
• 10.4 Structure-Passive Transcellular BBB Permeation Relationships
• 10.5 Structure Modification Strategies to Improve BBB Permeation
• 10.6 Applications of Brain Exposure
• Problems

Chapter 11: Metabolic Stability

• Abstract
• 11.1 Introduction
• 11.2 Metabolic Stability Fundamentals
• 11.3 Metabolic Stability Effects
• 11.4 Structure Modification Strategies for Phase I CYP Metabolic Stability
• 11.5 Structure Modification Strategies for Phase II Metabolic Stability
• 11.6 Applications of Metabolic Stability Data
• 11.7 Consequences of Chirality on Metabolic Stability
• 11.8 Substrate Specificity of CYP Isozymes
• 11.9 Aldehyde Oxidase
• Problems

Chapter 12: Plasma Stability

• Abstract
• 12.1 Introduction
• 12.2 Plasma Stability Fundamentals
• 12.3 Effects of Plasma Instability
• 12.4 Structure Modification Strategies to Improve Plasma Stability
• 12.5 Strategies for Plasma Stability
• Problems

Chapter 13: Solution Stability

• Abstract
• 13.1 Introduction
• 13.2 Solution Stability Fundamentals
• 13.3 Effects of Solution Instability
• 13.4 Solution Stability Case Studies
• 13.5 Structure Modification Strategies to Improve Solution Stability
• 13.6 Applications of Solution Stability in Drug Discovery
• Problems

Chapter 14: Plasma and Tissue Binding

• Abstract
• 14.1 Introduction
• 14.2 Drug Binding in Plasma
• 14.3 Drug Binding in Tissue
• 14.4 Free Drug Hypothesis
• 14.5 Pharmacokinetics Principles of Oral Drugs Relevant to Drug Binding
• 14.6 The Useful Application of f_u
• 14.7 Misconceptions and Unproductive Strategies for PPB
• 14.8 Best Practices Regarding PPB and Tissue Binding
• Problems

Chapter 15: Cytochrome P450 Inhibition

• Abstract
• 15.1 Introduction
• 15.2 CYP Inhibition Fundamentals
• 15.3 Effects of CYP Inhibition
• 15.4 CYP Inhibition Case Studies
• 15.5 Structure Modification Strategies to Reduce CYP Inhibition
• 15.6 Other DDIs
• 15.7 Regulatory Guidance on DDI
• 15.8 Applications of CYP Inhibition
• Problems

Chapter 16: hERG Blocking

• Abstract
• 16.1 Introduction
• 16.2 hERG Fundamentals
• 16.3 hERG Blocking Effects
• 16.4 hERG Blocking SAR
• 16.5 Structure Modification Strategies for hERG
• 16.6 Applications of hERG Blocking Assessment
• Problems

Chapter 17: Toxicity

• Abstract
• 17.1 Introduction
• 17.2 Toxicity Fundamentals
• 17.3 Toxic Effect Categories
• 17.4 Examples of Toxicity Effects
• 17.5 In Vivo Toxicity
• 17.6 Case Studies of Toxicity in Drug Discovery
• 17.7 Rules for Off-Target Toxicity by Drug Discovery Compounds
• 17.8 Relationship of C_max to in vivo Toxicity of Drug Discovery Compounds
• 17.9 Structure Modification Strategies to Improve Safety
• Problems

Chapter 18: Integrity and Purity

• Abstract
• 18.1 Introduction
• 18.2 Fundamentals of Integrity and Purity
• 18.3 Integrity and Purity Effects
• 18.4 Applications of Integrity and Purity
• Problems

Chapter 19: Pharmacokinetics

• Abstract
• 19.1 Introduction
• 19.2 PK Parameters
• 19.3 Tissue Concentration
• 19.4 Using PK Data in Drug Discovery
• 19.5 Relationship of PK to PD
• 19.6 Applications of PK
• Problems

Chapter 20: Lead Properties

• Abstract
• 20.1 Introduction
• 20.2 Lead-like Properties
• 20.3 Template Property Conservation
• 20.4 Including Properties in Hit Triage
• 20.5 Fragment-based Screening
• 20.6 Ligand Lipophilicity Efficiency
• 20.7 Conclusions
• Problems

Chapter 21: Strategies for Integrating Drug-Like Properties into Drug Discovery

• Abstract
• 21.1 Introduction
• 21.2 Start Assessing Drug Properties Early to Prioritize Compounds and Plan Structure Modifications
• 21.3 Assess Drug Properties for all New Compounds Rapidly
• 21.4 Develop Structure-Property Relationships
• 21.5 Optimize Activity and Properties in Parallel
• 21.6 Use Single-property Assays to Guide Specific Modifications
• 21.7 Use Complex Property Methods for Decision-making and Human Modeling
• 21.8 Apply Property Data to Improve Biological Experiments
• 21.9 Use Customized Assays to Answer Specific Research Questions
• 21.10 Diagnose the Root Cause of Inadequate Pharmacokinetics
• 21.11 Run in vitro Assays Using Human Materials to Predict Human Performance
• Problems

Chapter 22: Methods for Profiling Drug-Like Properties: General Concepts

• Abstract
• 22.1 Introduction
• 22.2 It is Valuable for Medicinal Chemists to Understand the ADMET Assays and Collaborate with ADMET Scientists
• 22.3 Choose an Ensemble of Key Properties to Evaluate
• 22.4 Use Relevant Assay Conditions
• 22.5 Property Data Should Be Readily Available
• 22.6 Evaluate the Cost-benefit Ratio for Assays
• 22.7 Use Well Developed Assays that Are Well Validated
• Problems

Chapter 23: Lipophilicity Methods

• Abstract
• 23.1 In Silico Lipophilicity Methods
• 23.2 Lipophilicity Methods
• 23.3 In-Depth Lipophilicity Methods
• Problems

Chapter 24: pK_a Methods

• Abstract
• 24.1 Introduction
• 24.2 In Silico pK_a Methods
• 24.3 Laboratory pK_a Methods
• Problems

Chapter 25: Solubility Methods

• Abstract
• 25.1 Introduction
• 25.2 Solubility Calculation Estimation
• 25.3 Software for Solubility
• 25.4 Kinetic Solubility Methods
• 25.5 Thermodynamic Solubility Methods
• 25.6 Customized Solubility Methods
• 25.7 Dissolution Rate Measurement
• 25.8 DMSO Solubility
• 25.9 Commercial CRO Labs Offering Solubility Measurement
• 25.10 Strategy for Solubility Measurement
• Problems

Chapter 26: Permeability Methods

• Abstract
• 26.1 Introduction
• 26.2 Computational Prediction of Permeability
• 26.3 In Vitro Permeability Methods
• 26.4 In-Depth Permeability Methods
• 26.5 Applications of Permeability in Drug Discovery
• Problems

Chapter 27: Transporter Methods

• Abstract
• 27.1 Introduction
• 27.2 In Silico Transporter Methods
• 27.3 In Vitro Transporter Methods
• 27.4 In Vivo Methods for Transporters
• Problems

Chapter 28: Blood-Brain Barrier Methods

• Abstract
• 28.1 Introduction
• 28.2 Methods for BBB Permeability
• 28.3 Methods for Brain Binding and Distribution
• 28.4 Applications of BBB Permeation and Brain Distribution Methods
• Problems

Chapter 29: Metabolic Stability Methods

• Abstract
• 29.1 Introduction
• 29.2 Metabolic Stability Methods
• 29.3 In Silico Metabolic Stability Methods
• 29.4 In Vitro Metabolic Stability Methods
• Problems

Chapter 30: Plasma Stability Methods

• Abstract
• 30.1 Introduction
• 30.2 General Protocol for in vitro Plasma Stability
• 30.3 Low-throughput Method for in vitro Plasma Stability
• 30.4 High-throughput Method for in vitro Plasma Stability
• 30.5 Structure Elucidation of Plasma Degradation Products
• 30.6 Strategies for Plasma Stability Measurement
• Problems

Chapter 31: Solution Stability Methods

• Abstract
• 31.1 Introduction
• 31.2 Methodology for Solution Stability Measurement
• 31.3 Method for Solution Stability in Biological Assay Media
• 31.4 Example Methods from the Literature for pH Solution Stability
• 31.5 Methods for Solution Stability in Simulated GI Fluids
• 31.6 Identification of Degradation Products from Solution Stability Assays
• 31.7 In-depth Solution Stability Assessment in Late Stage Drug Discovery
• 31.8 Strategy for Solution Stability Assessment
• Problems

Chapter 32: CYP Inhibition Methods

• Abstract
• 32.1 Introduction
• 32.2 In Silico CYP Inhibition Methods
• 32.3 In Vitro Reversible CYP Inhibition Methods
• 32.4 In Vitro Irreversible (TDI) CYP Inhibition Methods
• 32.5 CYP Inhibition Method Applications
• Problems

Chapter 33: Plasma and Tissue Binding Methods

• Abstract
• 33.1 Introduction
• 33.2 In Silico Plasma Protein Binding Methods
• 33.3 In Vitro Binding Methods
• 33.4 Red Blood Cell Binding
• 33.5 Contract Research Laboratories for Protein Binding Assays
• Problems

Chapter 34: hERG Methods

• Abstract
• 34.1 Introduction
• 34.2 In Silico hERG Methods
• 34.3 In Vitro hERG Methods
• 34.4 Ex Vivo Methods for hERG Blocking
• 34.5 In Vivo Electrocardiography Telemetry for hERG Blocking
• 34.6 Applications of hERG Blocking Methods in Drug Discovery
• Problems

Chapter 35: Toxicity Methods

• Abstract
• 35.1 Introduction
• 35.2 In Silico Toxicity Methods
• 35.3 In Vitro Toxicity Methods
• 35.4 In Vivo Toxicity Methods
• Problems

Chapter 36: Integrity and Purity Methods

• Abstract
• 36.1 Introduction
• 36.2 Samples for Integrity and Purity Profiling
• 36.3 Requirements of Integrity and Purity Profiling Methods
• 36.4 Integrity and Purity Method Characteristics
• 36.5 Follow Up on Negative Identity Results
• 36.6 Example Generic High-Throughput Purity and Integrity Method
• 36.7 Purity and Integrity Case Studies
• Problems

Chapter 37: Pharmacokinetic Methods

• Abstract
• 37.1 Introduction
• 37.2 Dosing for PK Studies
• 37.3 PK Sampling and Sample Preparation
• 37.4 LC/MS/MS Analysis
• 37.5 Advanced PK Studies
• 37.6 Example Pharmacokinetic Data
• 37.7 Tissue Penetration
• 37.8 Unbound Drug Concentration in Plasma or Tissue
• 37.9 Contract Research Laboratories
• Problems

Chapter 38: Diagnosing and Improving Pharmacokinetic Performance

• Abstract
• 38.1 Introduction
• 38.2 Diagnosing Underlying Property Limitations from PK Performance
• 38.3 Case Studies on Diagnosing Unfavorable PK Behavior
• Problems

Chapter 39: Prodrugs

• Abstract
• 39.1 Introduction
• 39.2 Prodrug Design Differs with the ADME Process and Administration Route
• 39.3 Using Prodrugs to Improve Solubility
• 39.4 Prodrugs to Increase Passive Permeability
• 39.5 Transporter-Mediated Prodrugs to Enhance Intestinal Absorption
• 39.6 Prodrugs to Reduce Metabolism
• 39.7 Prodrugs to Target Specific Tissues
• 39.8 Soft Drugs
• Problems

Chapter 40: Effects of Properties on Biological Assays

• Abstract
• 40.1 Introduction
• 40.2 Effects of Insolubility in DMSO
• 40.3 Dealing with Insolubility in DMSO
• 40.4 Effects of Insolubility in Aqueous Buffers
• 40.5 Dealing with Insolubility in Aqueous Buffers
• Problems

Chapter 41: Formulation

• Abstract
• 41.1 Introduction
• 41.2 Routes of Administration
• 41.3 Potency Drives Delivery Opportunities
• 41.4 Formulation Strategies
• 41.5 Practical Guide for Formulation in Drug Discovery
• Problems

Appendix I: Answers to Chapter Problems

• Chapter 1—Introduction
• Chapter 2—Benefits of Property Assessment and Good Drug-like Properties
• Chapter 3—In Vivo Environments Affect Drug Exposure
• Chapter 4—Prediction Rules for Rapid Property Profiling From Structure
• Chapter 5—Lipophilicity
• Chapter 6—pK_a
• Chapter 7—Solubility
• Chapter 8—Permeability
• Chapter 9—Transporters
• Chapter 10—Blood-Brain Barrier
• Chapter 11—Metabolic Stability
• Chapter 12—Plasma Stability
• Chapter 13—Solution Stability
• Chapter 14—Plasma Protein Binding
• Chapter 15—Cytochrome P450 Inhibition
• Chapter 16—hERG Blocking
• Chapter 17—Toxicity
• Chapter 18—Purity and Integrity
• Chapter 19—Pharmacokinetics
• Chapter 20—Lead Properties
• Chapter 21—Strategies for Integrating Drug-like Properties into Drug Discovery
• Chapter 22—Methods for Profiling Drug-like Properties: General Concepts
• Chapter 23—Lipophilicity Methods
• Chapter 24—pK_a Methods
• Chapter 25—Solubility Methods
• Chapter 26—Permeability Methods
• Chapter 27—Transporter Methods
• Chapter 28—Blood-Brain Barrier Methods
• Chapter 29—Metabolic Stability Methods
• Chapter 30—Plasma Stability Methods
• Chapter 31—Solution Stability Methods
• Chapter 32—CYP Inhibition Methods
• Chapter 33—Plasma Tissue Binding Methods
• Chapter 34—hERG Methods
• Chapter 35—Toxicity Methods
• Chapter 36—Integrity and Purity Methods
• Chapter 37—Pharmacokinetic Methods
• Chapter 38—Diagnosing and Improving Pharmacokinetic Performance
• Chapter 39—Prodrugs
• Chapter 40—Effects of Properties on Biological Assays
• Chapter 41—FORMULATION

Appendix II: General Reference Books

Appendix III: Glossary

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