Contents

Preface V

A Personal Foreword VII

List of Contributors IX

1 Lipophilicity: The Empirical Tool and the Fundamental Objective.

An Introduction 1

V. Pliska, B. Testa and H. Van de Waterbeemd

1.1 Setting the Scene 1

1.2 Biological Aspects 1

1.3 The Molecule in the Background 2

1.4 Some Pragmatic Aspects 3

1.4.1 Definitions and Symbols 3

1.4.2 Experimental Techniques 4

1.4.3 Computational Procedures 5

1.5 Objectives of the Book 5

References 6

2 Lipophilicity: A History 7

2.1 Introduction 7

2.2 Measurement of Lipophilicity 9

2.3 Calculation of Lipophilicity 11

2.3.1 Substitution Method 11

2.3.2 Fragment Additivity Method 12

2.3.3 Fragmentation into Atoms 13

2.3.4 Molecular Orbital Calculations 14

2.3.5 Calculations Based on Surface Area 14

2.4 The Nature of Lipophilicity 17

2.4.1 Relation to Other Molecular Properties 18

2.4.2 Thermodynamics of Partitioning 19

2.4.2.2 The Aqueous Phase and the "Hydrophobic Bond" 21

2.5 Lipophilicity and Biological Activity 22

References 24

3 Thermodynamics of van der Waals and Hydrophobic Interactions 27

R. Zahradnik and P. Hobza

3.1 Introduction 28

3.2 Outline of Thermodynamics and Auxiliary Disciplines 31

3.3 Intermolecular Interactions of the van der Waals Type 33

3.3.1 The Physical Nature of van der Waals Interactions 33

3.3.2 Classification of van der Waals Clusters 34

3.3.3 Calculation of the Interaction Energy 34

3.3.3.1 Nonempirical ab initio Variational Method 35

3.3.3.2 Density Functional Theory 36

3.3.3.3 Semiempirical Methods 36

3.3.3.4 Empirical Procedures 36

3.3.4 How to Obtain a Consistent Set of Various Calculated Properties for van der Waals Clusters 37

3.3.4.2 Stabilization Energy 37

3.3.4.3 Empirical Potential 38

3.3.4.4 Vibration Frequencies 38

3.3.4.5 Computer Experiments 38

3.4 Processes Involving Hydrophobic Effects 38

3.5 Specific Illustrations 40

3.5.1 Ab initio Evaluation of a Consistent Set of Various

Properties of the Benzene... Arn Cluster 40

3.5.1.1 Potential Energy Surface 40

3.5.1.2 More Accurate Calculations for the Global Minimum 41

3.5.1.3 Preparation of the Empirical Potential 41

3.5.1.4 Vibrational Frequencies 42

3.5.1.5 Molecular Dynamics Simulations 42

3.5.2 Monte Carlo Free Energy Perturbation Calculation: Solvation Free

Energy of Methanol and Ethane 43

References 43

Appendices 45

4 Intramolecular Interactions Encoded in Lipophilicity:

Their Nature and Significance 49

B. Testa, P.-A. Carrupt, P. Gaillard and R.-S. Tsai

4.1. Introduction : The Concept of Molecular Structure 49

4.1.1 The Elementary and Geometric Levels of Description 49

4.1.2 The Stereoelectronic Levels of Description 50

4.1.3 Social Molecules 51

4.2 Intermolecular Forces Encoded in Lipophilicity 52

4.2.1 Recognition Forces in Molecular Pharmacology and Biology 52

4.2.2 Factorization of Molecular Lipophilicity 53

4.2.3 Polar Interactions Encoded in Lipophilicity 54

4.2.4 Nonpolar Interactions Encoded in Lipophilicity 55

4.2.5 Recognition Forces Encoded in Lipophilicity 55

4.3 Intramolecular Interactions Affecting Lipophilicity 55

4.3.1 Electronic Conjugations 56

4.3.1.1 In Aromatic Systems 56

4.3.1.2 Across Aliphatic Segments 57

4.3.2 Interactions Involving Polar Groups 58

4.3.2.1 Proximity Effects Between Two Neutral Polar Groups 58

4.3.2.3 The Case of Zwitterions 61

4.3.2.4 Hydrophilic Collapse 62

4.3.2.5 Proximity Effects Between Polar and Nonpolar Groups 63

4.3.3 Steric/Hydrophobic Effects 64

4.3.3.1 Shielding of Polar Groups 64

4.3.3.3 Hydrophobic Collapse 65

4.4 Structural Factors Influencing Intramolecular Interactions 65

4.4.1 Positional Isomerism 66

4.4.2 Stereoisomerism 67

4.4.3 Ionization 67

4.4.4 Molecular Size and Chameleonic Behavior 68

4.5 Outlook: Molecular Polymorphism in Drug Design 69

Acknowledgements 70

References 70

5 Lipophilicity Measurement by Reversed-Phase

High Performance Liquid Chromatography (RP-HPLC) 73

H. van de Waterbeemd, M. Kansy, B. Wagner and H. Fischer

5.1 Historical 74

5.2 Principle of Lipophilicity Measurements by RPLC 74

5.2.1 Description of the Method 74

5.3 Stationary Phases (Column Packings) 77

5.3.1 Overview 77

5.3.2 New HPLC Packing Materials for Lipophilicity Measurements 78

5.3.3 Column Length 78

5.4 Mobiles Phases 78

5.4.1 Selection of Organic Modifier 78

5.4.2 Buffer and the Effect of Ionization 79

5.4.2.2 Ionization Correction 79

5.4.3 Masking Agents 79

5.4.4 Ion Pairs and Ion Pair Chromatography (IPC) 80

5.5 Retention Mechanism 80

5.5.1 Solvatochromic Analysis 80

5.5.2 Slope Analysis and Hydrogen-Bonding Capacity 81

5.5.3 Effect of Intercharge Distance in Zwitterions 82

5.5.4 Effect of Conformation on Retention 82

5.5.5 Lipophilicity of Peptides and Proteins 83

5.6 Correlations of log kw Values to log Poa and Other log P Scales 83

5.7 Recommendations 85

5.7.1 OECD/EU Guidelines 85

5.7.2 Recommended Method 85

Acknowledgements 85

References 85

6 Centrifugal Partition Chromatography for Lipophilicity

Measurements 89

6.1 Introduction: a Need for an Accurate Method for Partition

Coefficient Measurements 89

6.2 Historical Aspects 91

6.2.1 The Discovery and Development of CPC . 91

6.2.2 From log Pocta„oi-hexa„e/water to log Poct Using Multichannel Cartridge-type CPC 92

6.2.3 From log P0ct to log P (Solvent "quartet") Using Coil

Planet-type CPC 92

6.3 Mechanisms of Solute Partitioning in Various Types of CPC 93

6.3.1 Hydrostatic Equilibrium Systems 93

6.3.2 Hydrodynamic Equilibrium Systems 95

6.4 Method Development for log P Measurements Using CPC 96

6.4.1 Calculation of Partition Coefficients 96

6.4.2 Considerations About the Equipment (Mainly the Centrifuge) 96

6.4.3 Experimental Design 98

6.5 Validation of log P Values Obtained from CPC 100

6.5.1 Partition Coefficients in n-OctanoI/Water Systems 101

6.5.2 Partition Coefficients in Alkane/Water Systems 101

6.5.3 Partition Coefficients in di-n-Butyl Ether/Water and Chloroform/

Water Systems 102

6.6 Application to the Determination of Solute Structural Properties ... 102

6.6.1 The Case of Zwitterionic Amino Acids 102

6.6.2 The Case of Anti-Dopaminergic 6-Methoxysalicylamides 104

6.7 Advantages and Limitations of the CPC Method for log P Measurements 104

6.8 Concluding Remarks 105

Acknowledgments 106

References 106

7 Assessment of Distribution-pH Profiles 109

A. Avdeef

7.1 Introduction 109

7.2 Partition Coefficient, log P, and the Dyrssen Two-Phase Titration . . 110

7.2.1 Historical Background 110

7.2.2 Titrations 110

7.2.3 Bjerrum Difference Plots 112

7.2.4 pH Definitions and Electrode Standardization 113

7.2.5 Definitions of Constants 114

7.3 Distribution Function (D) and the Lipophilicity Profile

7.3.1 Experimental Evidence for Ion-Pairing: Shake-Flask vs pH-Metric 118

7.3.2 Further Insights into the Scherrer p^a 121

7.3.3 pH Scale in Lipids? 122

7.3.4 Monoprotic Substance log D-pH Curve Shape Analysis 123

7.3.5 Application of Shape Analysis to One-Point log D Shake-Flask Measurement 123

7.3.6 Effect of Salt: Monoprotic Examples 126

7.3.7 Debye-Hückel Corrections to OctanolAVater Partition Constants . . 127

7.3.8 Diprotic Substance log Z)-pH Curve Shape Analysis (12 Cases) ... 128

7.3.9 Diprotic Molecules with Two Different Ion Pair Partitionings 129

7.3.10 Macro-p/£a, Micro-pATa, and Zwitterions 131

7.3.11 Relationship between Micro-log P, Macro-log p, and log D 132

7.3.12 Micro-log p Application 133

7.3.13 Partitioning of the Amino Acids Phenylalanine and Tryptophanylphenylalanine 133

7.3.14 Partitioning of Morphine Derivatives and Metabolites 135

7.3.15 Drug-Liposome Partitioning, First Look 136

7.4 Outlook 136

Acknowledgements 137

8 Estimation of Lipophilicity by Reversed-Phase Thin-Layer Chromatography 141

R. Mannhold, K. Dross and C. Sonntag

8.1 Introduction 141

8.2 Stationary Phase 143

8.3 Mobile Phase 145

8.3.1 The Influence of the Organic Modifier on Ru 145

8.3.2 The Influence of Solvent pH and Ionic Strength oni?M 145

8.4 /?Mw and Extrapolation Methods 146

8.4.1 Quadratic Function 147

8.4.2 Exponential Function 147

8.4.3 Mixed Exponential/Linear Function 148

8.5 Analysis of the RM/(\p Relation 148

8.6 Comparison with Other Lipophilicity Data 149

8.6.1 The Comparison of RMw with log 149

8.6.2 The Comparison of /?Mw with log P0a 149

8.6.3 The Comparison of 7?Mw with Calculated log P 152

8.7 Concluding Remarks 153

References 154

9 The Future of log P Calculation 157

9.1 Introduction 157

9.2 Methods 158

9.2.1 The Substituent Method 158

9.2.2 Atom-Based Methods 158

9.2.3 Methods Based on Molecular Properties 159

9.2.4 Fragment-Based Methods 161

9.3 Common Problems 161

9.3.1 How is the "True" Structure to be Represented? 161

9.3.2 Intramolecular H-bonding 165

9.4 Conclusions 170

References 171

10 Theoretical Calculation of Partition Coefficients 173

W. G. Richards

10.1 Introduction 173

10.2 Statistical Thermodynamics 174

10.3 Equilibrium Constants 174

10.4 Free Energy Perturbation Calculations 175

10.5 Partition Coefficients 176

10.6 Membrane Simulations 178

10.7 Future Outlook 180

References 180

11 Cellular Automata Model of Partitioning Between

Liquid Phases 181

11.1 Introduction 181

11.2 Cellular Automata 182

11.2.1 The Model 182

11.2.2 The Molecular System 183

11.2.3 The Dimensional Relationship in Cellular Automata Models 184

11.2.4 The Rules 184

11.3 Models of Solution Phenomena 185

11.3.1 A Model of Water 185

11.3.2 A Model of a Solution 186

11.3.3 A Model of the Hydrophobic Effect 186

11.3.4 A Model of Dissolution 186

11.4 A Cellular Automata Model of Immiscibility 187

11.4.1 Immiscible Liquids 187

11.4.2 A Model of Immiscible Systems 187

11.4.3 An Immiscible Liquid Simulation 188

11.5 A Model of Partitioning Between Immiscible Liquids 190

11.6 Conclusion 192

Acknowledgements 193

References 194

12 The Molecular Lipophilicity Potential (MLP): A New Tool for log P Calculations and Docking and in Comparative

Molecular Field Analysis (CoMFA) 195

P.-A. Corrupt, P. Gaillard, F. Billois, P. Weber, B. Testa, C. Meyer and S. Pérez

12.1 Computational Approaches to Lipophilicity 195

12.1.1 Introduction 195

12.1.2 Limits of Fragmental Systems 196

12.2 The Molecular Lipophilicity Potential (MLP): a Tool to Compute Partition Coefficients from 3D Structures 196

12.2.1 Derivation of the MLP 196

12.2.2 Back-Calculation of Partition Coefficient 197

12.3 The MLP: a Tool to Explore Conformational Effects on

Lipophilicity 198

12.3.1 Quenched Molecular Dynamics: an Effective Exploration of Conformational Space 198

12.3.2 Conformation-Dependent Variations in Lipophilicity as Described by the MLP 199

12.3.3 Applications 200

12.3.3.1 Lipophilicity Variation in GABA-receptor Antagonists 200

12.3.3.2 Lipophilicity of L-Dopa Esters 202

12.4 The MLP as a Docking Tool 204

12.4.1 Intrinsic MLP, Perceived MLP, and Similarities Between Them . . . 204

12.4.2 Applications 204

12.4.2.1 Binding Modes of some D2-receptor Agonists 204

12.4.2.2 Binding Modes of HEL (52-61) to the I-Ak MHC II Protein 206

12.5 The MLP as an Additional Field in 3D QSAR 208

12.5.1 Limits of Standard CoMFA Approaches 208

12.5.2 The MLP, a Third Field in CoMFA 209

12.5.2.1 Theory 209

12.5.2.2 Intercorrelations of CoMFA Results Obtained with

Different Fields 210

12.5.3 Applications 211

12.5.3.1 Binding to 5-HTIA Receptors 211

12.5.3.2 CoMFA Models of Sweetness in Halogenated Sucroses 213

12.6 Perspectives 214

Acknowledgements 215

References 215

Appendix 217

13 Hydrophobic Fields in Quantitative Structure-Activity Relationships 219

G. Folkers and A. Merz

13.1 Introduction 219

13.2 Definition 220

13.3 Fragmental Property Contributions 221

13.4 Algorithms for Calculation of Hydrophobic Fields 222

13.4.1 GRID 222

13.4.2 Molecular Lipophilicity Potential (MLP) 223

13.4.3 Hydrophobic Interaction Potential (HINT) 223

13.5 Combination of Hydrophobic Fields with 3D QSAR Techniques .. 224

13.6 Mechanistic Interpretation of Protein-Ligand Crystal Data 224

13.8 Experiments and Caveats 226

13.9 Outlook 230

References 231

14 Physico-Chemical and Biological Factors that Influence a

Drug's Cellular Permeability by Passive Diffusion 233

14.1 Introduction 233

14.1.1 Cellular Barriers to Drug Transport 234

14.1.2 Transport Pathways 235

14.1.2.1 Paracellular Transport 235

14.1.2.2 Transcellular Transport 236

14.2 Physico-Chemical Factors Influencing Transcellular Passive Diffusion 237

14.2.1 Predictive Partition Coefficients 240

14.2.2 Relationship to a Drug's Lipophilicity 241

14.2.3 Relationship to a Drug's Hydrogen Bonding Potential 242

14.2.3.1 Intestinal Mucosal Cell Transport 242

14.2.3.2 Blood-Brain Barrier Transport 245

14.2.3.3 Mechanistic Considerations 245

14.2.4 Relationship to a Drug's Solution Conformation . 246

14.3 Biological Factors Influencing Transcellular Passive Permeability: Polarized Efflux Systems 247

14.4 Rationally Designing Drugs with Enhanced Cellular Permeability . 249

Acknowledgements 249

References 250

15 Lipophilicity of Metabolites and Its Role in Biotransformation 253

15.1 Introduction 253

15.2 Introduction of a Lipophilic Group into a Drug 254

15.3 Introduction of a Polar Group into a Drug 256

15.3.1 Increase of Lipophilicity Following a Phase 1 Reaction 256

15.3.2 Increase of Lipophilicity Following a Phase 2 Reaction 257

15.4 Pharmacokinetic and Pharmacodynamic Consequences 259

References 261

16 The Role of Lipophilicity in Biological Response to Drugs and Endogenous Ligands 263

V Pliska

16.1 Introductory Comments and Definitions 265

16.2 Phases of a Biological Response 266

16.3 Stimulus-Response Profiles 267

16.3.1 Characteristic Types of Response Profiles 267

16.3.2 Time and Intensity Components of a Response 269

16.4 Bioactive Substance in the Receptor Compartment:

Response Function 269

16.4.1 General Formula of the Response Function 269

16.4.2 Transport and Partitioning 270

16.4.3 Compartmentation in the Vicinity of a Membrane 271

16.4.4 Partitioning in the Aqueous/Lipid Interphase on Cell Surface 272

16.5 Ligand-Receptor Interaction 274

16.6 Factors Determining Biological Responses: a Summary 277

16.7 Partial Agonism and the Role of Lipophilicity 277

16.7.1 Dose-Response Relationship and the Phenomenon of

"Partial Agonism" 277

16.7.2 Partial Agonism in Cholinergic Systems 279

16.7.3 Molecular Perturbation Hypotheses 280

16.7.4 "Wrong-Way" Binding Model of Partial Agonism 280

16.7.5 Effect of Lipophilicity on Intrinsic Activity 281

16.7.6 Other Examples of Full-to-Partial-Agonism Transition due to Lipophilicity Increase 282

16.8 Bell-Shaped Dose-Response Curves 283

16.9 Thermodynamic Aspects of Variable Intrinsic Activity 285

16.9.1 Hydrophobic Interactions as an Entropy-Driven Process 285

16.9.2 AS AH0 Relationships in Some Receptor Systems 286

16.9.2.1 Muscarinic Receptors 286

16.9.2.3 GABAa Receptors 289

16.9.2.4 Opioid Receptors 289

16.9.2.5 Adenosine A, Receptors 289

16.9.2.6 Dopamine D2 Receptors 290

16.9.3 Entropy-Enthalpy Compensation 290

16.10 Outlook 291

References 291

17 Membrane Transport and Cellular Distribution 295

17.1 Introduction 296

17.2 Model 297

17.2.1 Model Construction 297

17.2.2 Relation Between Individual Distribution Processes and

Drug Properties 298

17.2.2.1 Transport Through Phase Interface 298

17.2.2.2 Membrane Accumulation 299

17.2.2.3 Binding to Cell Constituents 299

17.2.2.4 Enzymatic and Spontaneous Reactions 299

17.3 Numerical Simulations 300

17.3.1 Closed Systems ! 302

17.3.1.1 Nonequilibrium Period 302

17.3.1.2 Equilibrium Period 303

17.3.1.3 Mixed Period 303

17.3.2 Open Systems 303

17.4 Explicit Descriptions 304

17.4.1 Nonionizable Compounds 305

17.4.2 Ionizable Compounds 306

17.4.3 Varying Acidity of the External Medium 307

17.5 Outlook 307

Acknowledgements 307

References 308

18 Applications of a Solvation Equation to Drug Transport Properties 311

18.1 Introduction 312

18.2 The Determination of Descriptors 315

18.3 Applications of the Solvation Equation 324

18.3.1 Seiler's Alog P Parameter 325

18.3.2 Reversed-phase HPLC 326

18.3.3 Water/Micelle Partition 327

18.3.4 The Blood-brain Barrier 328

18.3.5 Permeation Through Skin 331

18.4 Conclusions 335

References 335

19 Environmental Hazard Assessment Using Lipophilieity Data 339

19.1 Introduction 339

19.2 Historical Perspective 340

19.2.1 Nonlinear Relationship to Water Solubility 340

19.2.2 Relationship of Toxicity to Chain Length and Molecular Weight ... 340

19.2.3 Chemical Constitution Theory of Hypnotic Activity 341

19.2.5 Development of the Lipoid Theory of Narcosis 341

19.2.6 QSAR and More Quantitative Use of Lipophilieity Data 342

19.3 Toxicological Applications 342

19.3.1 Contributions of Lazarev 342

19.3.2 Development of QSAR in Aquatic Toxicology 344

19.3.3 Water Solubility and Pharmacokinetic Cutoff: QSAR Limitations . 345

19.3.4 Additive Effects of Toxicants 345

19.3.5 Bioconcentration 346

19.3.6 Thermodynamic Approaches 347

19.3.7 Excess Toxicity as a Measure of Specific Mechanism of Action . . . 347

19.3.7.1 Electrophile Toxicants 348

19.3.7.2 Proelectrophile Toxicants 348

19.3.7.3 CyanogenicToxicants 349

19.4 Biodégradation 350

19.5 Outlook 350

References 351

20 Lipophilieity in Peptide Chemistry and Peptide Drug Design 355

20.1 Introduction 355

20.2 Lipophilieity of Amino Acids and Parametrization of Side Chain Hydrophobicity 356

20.3 Lipophilieity of Peptides, Pseudopeptides and Mimetics 358

20.3.1 Experimental P Values for Peptides 358

20.3.2 Calculated Values of log P (log D) for Peptides 360

20.3.3 Pseudopeptides 362

20.3.4 Peptidomimetics 363

20.4 Lipophilieity and Peptide Conformation 364

20.4.1 Log P and Conformation 364

20.4.3 Amphipathic Secondary Structures 365

20.4.4 Hydrophobic Collapse 365

20.4.5 Molecular Lipophilieity Potential 366

20.5 Lipophilieity and Peptide Transport 366

20.5.1 Pharmacokinetic Properties 366

20.5.2 Hydrogen Bonding and Hydrophobicity 366

20.5.3 Prodrugs 368

20.6 Conclusion and Outlook 369

References 370

21 Side Chain Lipophilicity of Noncoded a-Amino Acids:

V. Pliska and E. Escher

21.1 Introduction 375

21.2 Lipophilicity Descriptor jt 376

21.3 Description of Tables 376

21.4 Newly Reported jr-values 377

21.5 Tables 378

References 386

22 The Application of the Intermolecular Force Model to Bioactivity, Peptide and Protein Quantitative Structure-Activity Relationships 387

M. Charton

22.1 Introduction 387

22.1.1 The Intermolecular Force (IMF) Equation 388

22.1.1.1 Intermolecular Force Parameterization 388

22.1.1.2 Steric Effect Parameterization 389

22.1.2 The Composition of the Side Chain Effect 390

22.1.3 The IMF Equation for Peptide and Protein Bioactivity 390

22.2 The IMF Method as a Bioactivity Model 390

22.2.1 The Hansch-Fujita Model 390

22.2.2 Alternatives to the Use of Lipophilicity Parameters 392

22.3 Bioactivity Model 392

22.4 Peptide Bioactivities 394

22.4.1 Types of Structural Variation in Peptides 394

22.4.2 Peptide QSARs 395

22.5 Protein Bioactivities 397

22.5.1 Types of Protein Bioactivity Data Sets 397

22.5.2 Protein QSAR 398

22.5.3 Limitation of the Model in Protein QSAR 398

References 399

23 Lipophilicity Descriptors for Structure-Property Correlation Studies: Overview of Experimental and Theoretical Methods and a Benchmark of log P Calculations 401

H. van de Waterbeemd and R. Mannhold

23.1 Introduction 402

23.2 Experimental Lipophilicity Scales 402

23.2.1 Shake-Flask Partitioning 402

23.2.1.1 Solvent/Water Systems 402

23.2.1.2 Aqueous Biphasic Systems 403

23.2.2 Chromatographic Methods 403

23.2.3 Alternative Experimental Methods 404

23.2.3.1 Slow Stirring 404

23.2.3.2 Filter Probe and Filter Chamber 405

23.2.3.3 Flow-Injection Extraction 405

23.2.3.4 Microscale Partitioning Apparatus 405

23.2.3.5 pH-Metric log P Determination 405

23.3 Calculated log P values 405

23.3.1 Overview 405

23.3.1.1 The jr-System 405

23.3.2.1 Calculation Method According to Ghose-Crippen 406

23.3.2.2 The HINT Approach of Abraham 407

23.3.2.3 The SMILOGP Approach of Dubost 407

23.3.3 BLOGP Methods 407

23.3.3.1 Conformation-Dependent log P calculations 408

23.3.4 CLOGP Methods 408

23.3.4.1 The 2f System of Rekker 408

23.3.4.2 CLOGP System of Hansch and Leo 408

23.3.4.3 Calculation Method According to Suzuki and Kudo 409

23.3.4.4 The CASE KLOGP Method 409

23.4 Comparison of log P Calculation Methods 409

23.4.1 A Benchmark of Simple Organic Compounds and Drugs 410

23.4.1.1 General Remarks 410

23.4.1.2 The Full Data Set 410

23.4.1.3 Subsets: Drugs and Simple Organic Compounds 411

23.5 Databases 411

23.5.1 Log F Databases 411

23.5.2 Substituent Values for Aliphatic and Aromatic Substituents 413

23.5.3 Lipophilicity Scales for Amino Acids 413

23.6 Perspectives 414

Acknowledgements 415

References 415

Index 419

Lipophilicity in Drug Action and Toxicology edited by Vladimir PliSka,Bernard Testa & Han van de Waterbeemd Copyright© VCH Verlagsgesellschaft mbH,1996

0 0

Post a comment