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Table of Contents
Preface to the Series; Preface; Contents; Physical Properties in Drug Design; 1 Introduction: The Realisation of Physical Property Issues; 1.1 Molecular Obesity and Obsession with Potency; 1.2 Med Chem Inflates Properties: The Body Doesnt́ Change; 2 Physical Properties: What Are They and Which Are Important?; 2.1 Lipophilicity/Hydrophobicity; 2.1.1 Small Hydrophilic Molecules: A Forgotten Strategy for Oral Medicines?; 2.1.2 Methods for the Measurement and Prediction of Lipophilicity; 2.1.3 Octanol Water Methods: Issues with Overly Lipophilic Compounds
2.1.4 Measurements Using Chromatographic Methods2.2 Acid/Base Strength: pKa; 2.2.1 Measurement and Calculation of pKa; 2.3 Solubility; 2.3.1 The General Solubility Equation; 2.3.2 Simulated Gastrointestinal Fluids; 2.4 Escape from Flatland and the Impact of Aromatic Ring Count; 2.4.1 Lipophilicity and Aromaticity Act in Unison; 3 How the Physical Environment of a Drug Changes from Administration to Target; 3.1 The Passage Through the Body for an Oral Medicine; 3.2 Oral Developability Classification System: Dose, Solubility and Permeation
4 Impact of Physical Properties on Developability and DMPK Parameters4.1 General Aspects of Lipophilicity-Dependent Behaviour; 4.2 Impact of logP, logDpH and Aromaticity on Particular Parameters; 4.2.1 Permeability; 4.2.2 Cytochrome P450s; 4.2.3 hERG Binding; 4.2.4 Promiscuity; 4.2.5 Human Serum Albumin Binding; 4.2.6 Intrinsic Clearance; 4.3 The Composite Risks of Poor Physical Profiles; 5 Efficiency Metrics and Their Interrelationship with Physical Properties; 5.1 Drug Efficiency; 5.1.1 Physical Estimates of Drug Efficiency; 5.2 Ligand Efficiency and Related Measures
5.3 Ligand Lipophilicity Efficiency Measures5.4 The Combined Influence of Efficiency Metrics and Physical Property Measures; 5.5 The Thermodynamics of Efficient Binding; 6 Conclusions; References; Improving Solubility via Structural Modification; 1 Introduction; 2 Description of Aqueous Solubility; 2.1 Definition of Solubility; 2.2 General Solubility Equation; 2.3 Solvation of Organic Molecules; 2.3.1 Effect of Molecular Size and Shape on Solvation; 2.3.2 Water-Solute Hydrogen Bonding; 2.4 Crystal Lattice Stability and Packing Efficiency; 2.4.1 Effect of Molecular Shape on Packing Efficiency
2.4.2 Intermolecular Interactions in the Solid State2.4.3 The Effect of Molecular Symmetry on Crystal Packing; 3 Tactics for Improving Solubility; 3.1 Reducing LogP; 3.1.1 Introducing a Solubilizing Appendage; Introducing Basic Appendages; Introducing Acidic Appendages; Introduction of Neutral Appendages; 3.1.2 Template and Substituent Modifications; Substituent Modifications; Analysis of Substituent Effects on Solubility; The Dual Nature of Fluorine; Intramolecular Interactions; Examples of Substituent Modifications; Template Modifications; 3.2 Disrupting Crystal Lattice Stability
2.1.4 Measurements Using Chromatographic Methods2.2 Acid/Base Strength: pKa; 2.2.1 Measurement and Calculation of pKa; 2.3 Solubility; 2.3.1 The General Solubility Equation; 2.3.2 Simulated Gastrointestinal Fluids; 2.4 Escape from Flatland and the Impact of Aromatic Ring Count; 2.4.1 Lipophilicity and Aromaticity Act in Unison; 3 How the Physical Environment of a Drug Changes from Administration to Target; 3.1 The Passage Through the Body for an Oral Medicine; 3.2 Oral Developability Classification System: Dose, Solubility and Permeation
4 Impact of Physical Properties on Developability and DMPK Parameters4.1 General Aspects of Lipophilicity-Dependent Behaviour; 4.2 Impact of logP, logDpH and Aromaticity on Particular Parameters; 4.2.1 Permeability; 4.2.2 Cytochrome P450s; 4.2.3 hERG Binding; 4.2.4 Promiscuity; 4.2.5 Human Serum Albumin Binding; 4.2.6 Intrinsic Clearance; 4.3 The Composite Risks of Poor Physical Profiles; 5 Efficiency Metrics and Their Interrelationship with Physical Properties; 5.1 Drug Efficiency; 5.1.1 Physical Estimates of Drug Efficiency; 5.2 Ligand Efficiency and Related Measures
5.3 Ligand Lipophilicity Efficiency Measures5.4 The Combined Influence of Efficiency Metrics and Physical Property Measures; 5.5 The Thermodynamics of Efficient Binding; 6 Conclusions; References; Improving Solubility via Structural Modification; 1 Introduction; 2 Description of Aqueous Solubility; 2.1 Definition of Solubility; 2.2 General Solubility Equation; 2.3 Solvation of Organic Molecules; 2.3.1 Effect of Molecular Size and Shape on Solvation; 2.3.2 Water-Solute Hydrogen Bonding; 2.4 Crystal Lattice Stability and Packing Efficiency; 2.4.1 Effect of Molecular Shape on Packing Efficiency
2.4.2 Intermolecular Interactions in the Solid State2.4.3 The Effect of Molecular Symmetry on Crystal Packing; 3 Tactics for Improving Solubility; 3.1 Reducing LogP; 3.1.1 Introducing a Solubilizing Appendage; Introducing Basic Appendages; Introducing Acidic Appendages; Introduction of Neutral Appendages; 3.1.2 Template and Substituent Modifications; Substituent Modifications; Analysis of Substituent Effects on Solubility; The Dual Nature of Fluorine; Intramolecular Interactions; Examples of Substituent Modifications; Template Modifications; 3.2 Disrupting Crystal Lattice Stability