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.

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.

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 DistributionLipophilicity 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 MoleculespH 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 DistributionSolubility 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

SolubilitypH 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 DistributionPermeability 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 DistributionAcid Dissociation ConstantpKa 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 DescriptorsAbsorption 213

Lipinski Rule of Five 214

Absorption Models with Lipophilicity and Size 217

Biopharmaceutics Classification System (BCS) 221

Absorption PotentialMaximum 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 DescriptorsDistribution 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 DescriptorsDrug Efficiency 303

Drug Efficiency 303

Summary 327

Questions for Review 327

References 328

12 Applications and Examples in Drug Discovery 330

StructureLipophilicity Relationships 330

StructureSolubility Relationships 346

StructurePermeability Relationships 354

StructureCharge State Relationships 362

StructureProtein Binding Relationships 366

StructurePhospholipid 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