Physicochemical and Biomimetic Properties in Drug Discovery

1 - PHYSICOCHEMICAL AND BIOMIMETIC PROPERTIES IN DRUG DISCOVERY: Chromatographic Techniques forLead Optimization [Seite 5]
2 - Copyright [Seite 6]
3 - CONTENTS [Seite 7]
4 - Preface [Seite 13]
5 - 1 The Drug Discovery Process [Seite 17]
5.1 - Summary [Seite 23]
5.2 - Question for Review [Seite 23]
5.3 - References [Seite 23]
6 - 2 Drug-Likeness and Physicochemical Property Spaceof Known Drugs [Seite 25]
6.1 - Summary [Seite 28]
6.2 - Questions for Review [Seite 29]
6.3 - References [Seite 29]
7 - 3 Basic Pharmacokinetic Properties [Seite 31]
7.1 - Absorption [Seite 33]
7.2 - Plasma Protein Binding [Seite 36]
7.3 - Distribution [Seite 38]
7.4 - Volume of Distribution [Seite 39]
7.5 - Unbound Volume of Distribution [Seite 45]
7.6 - Half-Life [Seite 46]
7.7 - Metabolism and Clearance [Seite 46]
7.8 - Free Drug Hypothesis [Seite 47]
7.9 - Summary [Seite 47]
7.10 - Questions for Review [Seite 48]
7.11 - References [Seite 49]
8 - 4 Principles and Methods of Chromatographyfor the Application of Property Measurements [Seite 50]
8.1 - Theoretical Background of Chromatography [Seite 51]
8.2 - Retention Factor and Its Relation to the Distribution Constant Betweenthe Mobile and the Stationary Phases [Seite 53]
8.3 - Measure of Separation Efficiency [Seite 56]
8.4 - Resolution and Separation Time [Seite 58]
8.5 - Gradient Elution [Seite 60]
8.6 - Applicability of Chromatography for Measurements of MolecularProperties [Seite 63]
8.7 - Summary [Seite 65]
8.8 - Questions for Review [Seite 66]
8.9 - References [Seite 66]
9 - 5 Molecular Physicochemical Properties that InfluenceAbsorption and Distribution-Lipophilicity [Seite 68]
9.1 - Partition Coefficient [Seite 68]
9.2 - Lipophilicity Measurements by Reversed Phase Chromatographywith Isocratic Elution [Seite 74]
9.3 - Lipophilicity Measurements by Reversed Phase Chromatographywith Gradient Elution [Seite 84]
9.3.1 - Typical Measurement Condition for Lipophilicity Determination byReversed Phase Gradient HPLC [Seite 86]
9.4 - Lipophilicity of Charged Molecules-pH Dependenceof Lipophilicity [Seite 88]
9.5 - Biomimetic Lipophilicity Measurements by Chromatography [Seite 94]
9.5.1 - Immobilized Human Serum Albumin (HSA) Stationary Phase [Seite 94]
9.5.2 - Typical Measurement Conditions of HSA Binding by HPLC Retention [Seite 98]
9.5.3 - Immobilized ?-1-Acid-glycoprotein (AGP) Stationary Phase [Seite 101]
9.5.4 - Typical Measurement Conditions of AGP Binding by HPLC Retention [Seite 102]
9.5.5 - Immobilized Artificial Membrane (IAM) Stationary Phase [Seite 103]
9.5.6 - Typical Measurement Conditions of IAM Binding by HPLC Retention [Seite 104]
9.6 - Comparing Various Lipophilicity Measures by the Solvation EquationModel [Seite 106]
9.7 - Summary [Seite 118]
9.8 - Questions for Review [Seite 121]
9.9 - References [Seite 121]
10 - 6 Molecular Physicochemical Properties that InfluenceAbsorption and Distribution-Solubility [Seite 128]
10.1 - Definition of Solubility [Seite 128]
10.2 - Molecular Interactions with Water [Seite 132]
10.3 - Various Solubility Measurements that can be Applied During the DrugDiscovery Process [Seite 135]
10.4 - Conditions that Affect Solubility [Seite 137]
10.5 - Solubility-pH Profile [Seite 148]
10.6 - Solubility and Dissolution in Biorelevant Media [Seite 150]
10.7 - Composition of Fasted State Simulated Intestinal Fluid (FaSSIF) [Seite 152]
10.8 - Preparation of FaSSIF Solution [Seite 152]
10.9 - Composition of Fed State Simulated Intestinal Fluid (FeSSIF) [Seite 152]
10.10 - Preparation of FeSSIF solution [Seite 152]
10.11 - Summary [Seite 159]
10.12 - Questions for Review [Seite 162]
10.13 - References [Seite 162]
11 - 7 Molecular Physicochemical Properties that InfluenceAbsorption and Distribution-Permeability [Seite 166]
11.1 - Biological Membranes [Seite 166]
11.2 - Artificial Membranes [Seite 169]
11.3 - Physicochemical Principles of Permeability [Seite 171]
11.4 - Experimental Methods to Measure Artificial MembranePermeability [Seite 175]
11.5 - Relationships Between Permeability, Lipophilicity, and Solubility [Seite 182]
11.6 - Chromatography as a Potential Tool for Measuring the Rate ofPermeation [Seite 187]
11.7 - Summary [Seite 191]
11.8 - Questions for Review [Seite 194]
11.9 - References [Seite 194]
12 - 8 Molecular Physicochemical Properties that InfluenceAbsorption and Distribution-Acid DissociationConstant-pKa [Seite 198]
12.1 - Definition of pKa [Seite 198]
12.2 - Methods for Determining pKa [Seite 204]
12.2.1 - Potentiometric Titration for the Determination of pKa [Seite 204]
12.3 - Spectrophotometric Determination of pKa [Seite 208]
12.4 - Determination of pKa by Capillary Electrophoresis [Seite 211]
12.5 - Chromatographic Approaches for the Determination of pKa [Seite 213]
12.6 - Summary [Seite 223]
12.7 - Questions for Review [Seite 225]
12.8 - References [Seite 225]
13 - 9 Models with Measured Physicochemical and BiomimeticChromatographic Descriptors-Absorption [Seite 229]
13.1 - Lipinski Rule of Five [Seite 230]
13.2 - Absorption Models with Lipophilicity and Size [Seite 233]
13.3 - Biopharmaceutics Classification System (BCS) [Seite 237]
13.4 - Absorption Potential-Maximum Absorbable Dose [Seite 243]
13.5 - Abraham Solvation Equations for Modeling Absorption [Seite 248]
13.6 - Effect of Active Transport and Metabolizing Enzymes on OralAbsorption and Bioavailability [Seite 251]
13.7 - Summary [Seite 252]
13.8 - Questions for Review [Seite 254]
13.9 - References [Seite 254]
14 - 10 Models with Measured Physicochemical and BiomimeticChromatographic Descriptors-Distribution [Seite 258]
14.1 - Models for Volume of Distribution [Seite 265]
14.2 - Plasma Protein Binding [Seite 292]
14.3 - Blood/Brain Distributions [Seite 304]
14.4 - Tissue Distribution [Seite 310]
14.5 - Summary [Seite 312]
14.6 - Questions for Review [Seite 314]
14.7 - References [Seite 314]
15 - 11 Models with Measured Physicochemical and BiomimeticChromatographic Descriptors-Drug Efficiency [Seite 319]
15.1 - Drug Efficiency [Seite 319]
15.2 - Summary [Seite 343]
15.3 - Questions for Review [Seite 343]
15.4 - References [Seite 344]
16 - 12 Applications and Examples in Drug Discovery [Seite 346]
16.1 - Structure-Lipophilicity Relationships [Seite 346]
16.2 - Structure-Solubility Relationships [Seite 362]
16.3 - Structure-Permeability Relationships [Seite 370]
16.4 - Structure-Charge State Relationships [Seite 378]
16.5 - Structure-Protein Binding Relationships [Seite 382]
16.6 - Structure-Phospholipid Binding Relationships [Seite 387]
16.7 - Summary [Seite 392]
16.8 - Questions for Review [Seite 395]
16.9 - References [Seite 395]
17 - Appendix A Answers to the Questions for Review [Seite 403]
18 - Appendix B List of Abbreviations and Symbols [Seite 443]
19 - Index [Seite 449]
20 - Supplemental Images [Seite 452]