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Drug-Like Properties,

Edition 2 Concepts, Structure Design and Methods from ADME to Toxicity Optimization

Editors: By Li Di and Edward H Kerns

Publication Date: 13 Jan 2016

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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.

Key Features

Provides a comprehensive and valuable working handbook for scientists and students in medicinal chemistry
Includes expanded coverage of pharmacokinetics fundamentals and effects
Contains updates throughout, including the authors’ recent work in the importance of solubility in drug development; new and currently used property methods, with a reduction of seldom-used methods; and exploration of computational modeling methods

About the author

By Li Di, Pfizer, East Lyme, CT, USA and Edward H Kerns, National Institutes of Health, Bethesda, MD, USA

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

ISBN: 9780128010761

Page Count: 580

Retail Price (USD) :

Blass, Basic Principles of Drug Discovery and Development, Academic Press, 2015, 9780124115088, $99.95
Redasani and Bari, Prodrug Design: Perspectives, Approaches and Applications in Medicinal Chemistry, Academic Press, 2015, 9780128035191, $49.95
Silverman and Holladay, The Organic Chemistry of Drug Design and Drug Action, Academic Press, 2014, 9780123820303, $99.95

Chemists (especially in medicinal chemistry, pharma/drug development, organic synthesis) and Drug researchers (including pharmacologists and toxicologists) in private industry, research centers and government labs. Secondary academic market with chemistry & pharmacology students.

Drug-Like Properties,

Editors: By Li Di and Edward H Kerns

Key Features

About the author

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