Drug-like Properties

* Dedication* 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: pKa* Abstract*6.1 pKa Fundamentals*6.2 pKa Effects*6.3 pKa Case Studies*6.4 Structure Modification Strategies for pKa* 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 fu*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 Cmax 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: pKa Methods* Abstract*24.1 Introduction*24.2 In Silico pKa Methods*24.3 Laboratory pKa 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-pKa* 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-pKa 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* Index