Physicochemical and Biomimetic Properties in Drug Discovery: Chromatographic Techniques for Lead Optimization

ISBN-13: 9781118152126 / Angielski / Twarda / 2014 / 450 str.

Klara Valko

Opis

Demonstrating how and why to measure physicochemical and biomimetic properties in early stages of drug discovery for lead optimization, Physicochemical and Biomimetic Properties in Drug Discovery encourages readers to discover relationships between various measurements and develop a sense of interdisciplinary thinking that will add to new research in drug discovery. This practical guide includes detailed descriptions of state-of-the-art chromatographic techniques and uses real-life examples and models to help medicinal chemists and scientists and advanced graduate students apply measurement data for optimal drug discovery.

Recenzje

This is one of those books that will not gather dust on the shelf (barring an epochal revolution in the field) because it will be a constant point of reference for established scientists participating in multidisciplinary pharmaceutical research teams or those who wish to establish themselves in this area.   (Doody s, 16 January 2015)

Spis treści

Preface xi

1 The Drug Discovery Process 1

Summary 7

Question for Review 7

References 7

2 Drug–Likeness and Physicochemical Property Space of Known Drugs 9

Summary 12

Questions for Review 13

References 13

3 Basic Pharmacokinetic Properties 15

Absorption 17

Plasma Protein Binding 20

Distribution 22

Volume of Distribution 23

Unbound Volume of Distribution 29

Half–Life 30

Metabolism and Clearance 30

Free Drug Hypothesis 31

Summary 31

Questions for Review 32

References 33

4 Principles and Methods of Chromatography for the Application of Property Measurements 34

Theoretical Background of Chromatography 35

Retention Factor and Its Relation to the Distribution Constant Between the Mobile and the Stationary
Phases 37

Measure of Separation Efficiency 40

Resolution and Separation Time 42

Gradient Elution 44

Applicability of Chromatography for Measurements of Molecular Properties 47

Summary 49

Questions for Review 50

References 50

5 Molecular Physicochemical Properties that Influence Absorption and Distribution Lipophilicity 52

Partition Coefficient 52

Lipophilicity Measurements by Reversed Phase Chromatography with Isocratic Elution 58

Lipophilicity Measurements by Reversed Phase Chromatography with Gradient Elution 68

Lipophilicity of Charged Molecules pH Dependence of Lipophilicity 72

Biomimetic Lipophilicity Measurements by Chromatography 78

Comparing Various Lipophilicity Measures by the Solvation Equation Model 90

Summary 102

Questions for Review 105

References 105

6 Molecular Physicochemical Properties that Influence Absorption and Distribution Solubility 112

Definition of Solubility 112

Molecular Interactions with Water 116

Various Solubility Measurements that can be Applied During the Drug Discovery Process 119

Conditions that Affect Solubility 121

Solubility pH Profile 132

Solubility and Dissolution in Biorelevant Media 134

Composition of Fasted State Simulated Intestinal Fluid (FaSSIF) 136

Preparation of FaSSIF Solution 136

Composition of Fed State Simulated Intestinal Fluid (FeSSIF) 136

Preparation of FeSSIF solution 136

Summary 143

Questions for Review 146

References 146

7 Molecular Physicochemical Properties that Influence Absorption and Distribution Permeability 150

Biological Membranes 150

Artificial Membranes 153

Physicochemical Principles of Permeability 155

Experimental Methods to Measure Artificial Membrane Permeability 159

Relationships Between Permeability, Lipophilicity, and Solubility 166

Chromatography as a Potential Tool for Measuring the Rate of Permeation 171

Summary 175

Questions for Review 178

References 178

8 Molecular Physicochemical Properties that Influence Absorption and Distribution Acid Dissociation Constant pKa 182

Definition of pKa 182

Methods for Determining pKa 188

Spectrophotometric Determination of pKa 192

Determination of pKa by Capillary Electrophoresis 195

Chromatographic Approaches for the Determination of pKa 197

Summary 207

Questions for Review 209

References 209

9 Models with Measured Physicochemical and Biomimetic Chromatographic Descriptors Absorption 213

Lipinski Rule of Five 214

Absorption Models with Lipophilicity and Size 217

Biopharmaceutics Classification System (BCS) 221

Absorption Potential Maximum Absorbable Dose 227

Abraham Solvation Equations for Modeling Absorption 232

Effect of Active Transport and Metabolizing Enzymes on Oral Absorption and Bioavailability 235

Summary 236

Questions for Review 238

References 238

10 Models with Measured Physicochemical and Biomimetic Chromatographic Descriptors Distribution 242

Models for Volume of Distribution 249

Plasma Protein Binding 276

Blood/Brain Distributions 288

Tissue Distribution 294

Summary 296

Questions for Review 298

References 298

11 Models with Measured Physicochemical and Biomimetic Chromatographic Descriptors Drug Efficiency 303

Drug Efficiency 303

Summary 327

Questions for Review 327

References 328

12 Applications and Examples in Drug Discovery 330

Structure Lipophilicity Relationships 330

Structure Solubility Relationships 346

Structure Permeability Relationships 354

Structure Charge State Relationships 362

Structure Protein Binding Relationships 366

Structure Phospholipid Binding Relationships 371

Summary 376

Questions for Review 379

References 379

Appendix A Answers to the Questions for Review 387

Appendix B List of Abbreviations and Symbols 427

Index 433

O autorze

KLARA VALKO is an Investigator in the Analytical Chemistry Department of Molecular Discovery Research at GlaxoSmithKline. Dr. Valko has more than thirty years of experience in HPLC, GC, and LC/MS. She also has more than ten years of experience teaching physicochemical measurements and ADME optimization tools at the UCL School of Pharmacy. Currently, Dr. Valko is an Honorary Professor, leading the Physchem/ADME module for a drug discovery MSc course.

Blurb

Explains how to take full advantage of chromatography to find successful drug candidates

Based on a course taught by the author for many years, this book demonstrates how to use chromatography to measure the physicochemical and biomimetic properties of drug candidates in the early stages of drug discovery in order to fully optimize drug leads. Readers will learn how to interpret chromatographic retention data using various models in order to estimate the in vivo distribution behavior of drugs. The property data obtained by these chromatographic measurements can then be used to select and prioritize compounds for further in vitro and in vivo studies at the early stages of the drug discovery process.

Physicochemical and Biomimetic Properties in Drug Discovery provides clear explanations and guidance to facilitate reproduction of the chromatographic measurements discussed in the book in any laboratory equipped with HPLC. It begins with a quick review of the drug discovery process. Next, it covers:

• Drug–likeness and the physicochemical property space of known drugs
• Basic pharmacokinetic properties
• Principles and methods of chromatography for the application of property measurements
• Molecular physicochemical properties that influence absorption and distribution: lipophilicity, solubility, permeability, and acid dissociation constant (pK_a)
• Models with measured physicochemical and biomimetic chromatographic descriptors: absorption, distribution, and drug efficiency

The final chapter is dedicated to applications and examples of the use of chromatography in drug discovery.

Throughout the book, real–life examples demonstrate how to optimize the use of chromatography to obtain successful drug candidates. Each chapter concludes with a series of questions, with answers in the appendix, making this book ideal for students as well as researchers in drug discovery.