{"product_id":"physicochemical-and-biomimetic-properties-in-drug-discovery-isbn-9781118152126","title":"Physicochemical and Biomimetic Properties in Drug Discovery","description":"\u003cp\u003eDemonstrating how and why to measure physicochemical and biomimetic properties in early stages of drug discovery for lead optimization, \u003ci\u003ePhysicochemical and Biomimetic Properties in Drug Discovery\u003c\/i\u003e 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.\u003c\/p\u003e  \u003cp\u003e\u003cb\u003ePreface xi\u003c\/b\u003e\u003c\/p\u003e \u003cp\u003e\u003cb\u003e1 The Drug Discovery Process 1\u003c\/b\u003e\u003c\/p\u003e \u003cp\u003eSummary 7\u003c\/p\u003e \u003cp\u003eQuestion for Review 7\u003c\/p\u003e \u003cp\u003eReferences 7\u003c\/p\u003e \u003cp\u003e\u003cb\u003e2 Drug-Likeness and Physicochemical Property Space of Known Drugs 9\u003c\/b\u003e\u003c\/p\u003e \u003cp\u003eSummary 12\u003c\/p\u003e \u003cp\u003eQuestions for Review 13\u003c\/p\u003e \u003cp\u003eReferences 13\u003c\/p\u003e \u003cp\u003e\u003cb\u003e3 Basic Pharmacokinetic Properties 15\u003c\/b\u003e\u003c\/p\u003e \u003cp\u003eAbsorption 17\u003c\/p\u003e \u003cp\u003ePlasma Protein Binding 20\u003c\/p\u003e \u003cp\u003eDistribution 22\u003c\/p\u003e \u003cp\u003eVolume of Distribution 23\u003c\/p\u003e \u003cp\u003eUnbound Volume of Distribution 29\u003c\/p\u003e \u003cp\u003eHalf-Life 30\u003c\/p\u003e \u003cp\u003eMetabolism and Clearance 30\u003c\/p\u003e \u003cp\u003eFree Drug Hypothesis 31\u003c\/p\u003e \u003cp\u003eSummary 31\u003c\/p\u003e \u003cp\u003eQuestions for Review 32\u003c\/p\u003e \u003cp\u003eReferences 33\u003c\/p\u003e \u003cp\u003e\u003cb\u003e4 Principles and Methods of Chromatography for the Application of Property Measurements 34\u003c\/b\u003e\u003c\/p\u003e \u003cp\u003eTheoretical Background of Chromatography 35\u003c\/p\u003e \u003cp\u003eRetention Factor and Its Relation to the Distribution Constant Between the Mobile and the Stationary\u003cbr\u003e Phases 37\u003c\/p\u003e \u003cp\u003eMeasure of Separation Efficiency 40\u003c\/p\u003e \u003cp\u003eResolution and Separation Time 42\u003c\/p\u003e \u003cp\u003eGradient Elution 44\u003c\/p\u003e \u003cp\u003eApplicability of Chromatography for Measurements of Molecular Properties 47\u003c\/p\u003e \u003cp\u003eSummary 49\u003c\/p\u003e \u003cp\u003eQuestions for Review 50\u003c\/p\u003e \u003cp\u003eReferences 50\u003c\/p\u003e \u003cp\u003e\u003cb\u003e5 Molecular Physicochemical Properties that Influence Absorption and Distribution—Lipophilicity 52\u003c\/b\u003e\u003c\/p\u003e \u003cp\u003ePartition Coefficient 52\u003c\/p\u003e \u003cp\u003eLipophilicity Measurements by Reversed Phase Chromatography with Isocratic Elution 58\u003c\/p\u003e \u003cp\u003eLipophilicity Measurements by Reversed Phase Chromatography with Gradient Elution 68\u003c\/p\u003e \u003cp\u003eLipophilicity of Charged Molecules—pH Dependence of Lipophilicity 72\u003c\/p\u003e \u003cp\u003eBiomimetic Lipophilicity Measurements by Chromatography 78\u003c\/p\u003e \u003cp\u003eComparing Various Lipophilicity Measures by the Solvation Equation Model 90\u003c\/p\u003e \u003cp\u003eSummary 102\u003c\/p\u003e \u003cp\u003eQuestions for Review 105\u003c\/p\u003e \u003cp\u003eReferences 105\u003c\/p\u003e \u003cp\u003e\u003cb\u003e6 Molecular Physicochemical Properties that Influence Absorption and Distribution—Solubility 112\u003c\/b\u003e\u003c\/p\u003e \u003cp\u003eDefinition of Solubility 112\u003c\/p\u003e \u003cp\u003eMolecular Interactions with Water 116\u003c\/p\u003e \u003cp\u003eVarious Solubility Measurements that can be Applied During the Drug Discovery Process 119\u003c\/p\u003e \u003cp\u003eConditions that Affect Solubility 121\u003c\/p\u003e \u003cp\u003eSolubility–pH Profile 132\u003c\/p\u003e \u003cp\u003eSolubility and Dissolution in Biorelevant Media 134\u003c\/p\u003e \u003cp\u003eComposition of Fasted State Simulated Intestinal Fluid (FaSSIF) 136\u003c\/p\u003e \u003cp\u003ePreparation of FaSSIF Solution 136\u003c\/p\u003e \u003cp\u003eComposition of Fed State Simulated Intestinal Fluid (FeSSIF) 136\u003c\/p\u003e \u003cp\u003ePreparation of FeSSIF solution 136\u003c\/p\u003e \u003cp\u003eSummary 143\u003c\/p\u003e \u003cp\u003eQuestions for Review 146\u003c\/p\u003e \u003cp\u003eReferences 146\u003c\/p\u003e \u003cp\u003e\u003cb\u003e7 Molecular Physicochemical Properties that Influence Absorption and Distribution—Permeability 150\u003c\/b\u003e\u003c\/p\u003e \u003cp\u003eBiological Membranes 150\u003c\/p\u003e \u003cp\u003eArtificial Membranes 153\u003c\/p\u003e \u003cp\u003ePhysicochemical Principles of Permeability 155\u003c\/p\u003e \u003cp\u003eExperimental Methods to Measure Artificial Membrane Permeability 159\u003c\/p\u003e \u003cp\u003eRelationships Between Permeability, Lipophilicity, and Solubility 166\u003c\/p\u003e \u003cp\u003eChromatography as a Potential Tool for Measuring the Rate of Permeation 171\u003c\/p\u003e \u003cp\u003eSummary 175\u003c\/p\u003e \u003cp\u003eQuestions for Review 178\u003c\/p\u003e \u003cp\u003eReferences 178\u003c\/p\u003e \u003cp\u003e\u003cb\u003e8 Molecular Physicochemical Properties that Influence Absorption and Distribution—Acid Dissociation Constant—pKa 182\u003c\/b\u003e\u003c\/p\u003e \u003cp\u003eDefinition of pKa 182\u003c\/p\u003e \u003cp\u003eMethods for Determining pKa 188\u003c\/p\u003e \u003cp\u003eSpectrophotometric Determination of pKa 192\u003c\/p\u003e \u003cp\u003eDetermination of pKa by Capillary Electrophoresis 195\u003c\/p\u003e \u003cp\u003eChromatographic Approaches for the Determination of pKa 197\u003c\/p\u003e \u003cp\u003eSummary 207\u003c\/p\u003e \u003cp\u003eQuestions for Review 209\u003c\/p\u003e \u003cp\u003eReferences 209\u003c\/p\u003e \u003cp\u003e\u003cb\u003e9 Models with Measured Physicochemical and Biomimetic Chromatographic Descriptors—Absorption 213\u003c\/b\u003e\u003c\/p\u003e \u003cp\u003eLipinski Rule of Five 214\u003c\/p\u003e \u003cp\u003eAbsorption Models with Lipophilicity and Size 217\u003c\/p\u003e \u003cp\u003eBiopharmaceutics Classification System (BCS) 221\u003c\/p\u003e \u003cp\u003eAbsorption Potential—Maximum Absorbable Dose 227\u003c\/p\u003e \u003cp\u003eAbraham Solvation Equations for Modeling Absorption 232\u003c\/p\u003e \u003cp\u003eEffect of Active Transport and Metabolizing Enzymes on Oral Absorption and Bioavailability 235\u003c\/p\u003e \u003cp\u003eSummary 236\u003c\/p\u003e \u003cp\u003eQuestions for Review 238\u003c\/p\u003e \u003cp\u003eReferences 238\u003c\/p\u003e \u003cp\u003e\u003cb\u003e10 Models with Measured Physicochemical and Biomimetic Chromatographic Descriptors—Distribution 242\u003c\/b\u003e\u003c\/p\u003e \u003cp\u003eModels for Volume of Distribution 249\u003c\/p\u003e \u003cp\u003ePlasma Protein Binding 276\u003c\/p\u003e \u003cp\u003eBlood\/Brain Distributions 288\u003c\/p\u003e \u003cp\u003eTissue Distribution 294\u003c\/p\u003e \u003cp\u003eSummary 296\u003c\/p\u003e \u003cp\u003eQuestions for Review 298\u003c\/p\u003e \u003cp\u003eReferences 298\u003c\/p\u003e \u003cp\u003e\u003cb\u003e11 Models with Measured Physicochemical and Biomimetic Chromatographic Descriptors—Drug Efficiency 303\u003c\/b\u003e\u003c\/p\u003e \u003cp\u003eDrug Efficiency 303\u003c\/p\u003e \u003cp\u003eSummary 327\u003c\/p\u003e \u003cp\u003eQuestions for Review 327\u003c\/p\u003e \u003cp\u003eReferences 328\u003c\/p\u003e \u003cp\u003e\u003cb\u003e12 Applications and Examples in Drug Discovery 330\u003c\/b\u003e\u003c\/p\u003e \u003cp\u003eStructure–Lipophilicity Relationships 330\u003c\/p\u003e \u003cp\u003eStructure–Solubility Relationships 346\u003c\/p\u003e \u003cp\u003eStructure–Permeability Relationships 354\u003c\/p\u003e \u003cp\u003eStructure–Charge State Relationships 362\u003c\/p\u003e \u003cp\u003eStructure–Protein Binding Relationships 366\u003c\/p\u003e \u003cp\u003eStructure–Phospholipid Binding Relationships 371\u003c\/p\u003e \u003cp\u003eSummary 376\u003c\/p\u003e \u003cp\u003eQuestions for Review 379\u003c\/p\u003e \u003cp\u003eReferences 379\u003c\/p\u003e \u003cp\u003e\u003cb\u003eAppendix A Answers to the Questions for Review 387\u003c\/b\u003e\u003c\/p\u003e \u003cp\u003e\u003cb\u003eAppendix B List of Abbreviations and Symbols 427\u003c\/b\u003e\u003c\/p\u003e \u003cp\u003e\u003cb\u003eIndex 433\u003c\/b\u003e\u003c\/p\u003e \u003cp\u003e“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.”  (\u003ci\u003eDoody’s\u003c\/i\u003e, 16 January 2015)\u003c\/p\u003e  \u003cp\u003e\u003cb\u003eKLARA VALKO\u003c\/b\u003e 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.\u003c\/p\u003e  \u003cp\u003e\u003cb\u003eExplains how to take full advantage of chromatography to find successful drug candidates\u003c\/b\u003e\u003c\/p\u003e \u003cp\u003eBased 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 \u003ci\u003ein vivo\u003c\/i\u003e distribution behavior of drugs. The property data obtained by these chromatographic measurements can then be used to select and prioritize compounds for further \u003ci\u003ein vitro\u003c\/i\u003e and \u003ci\u003ein vivo\u003c\/i\u003e studies at the early stages of the drug discovery process.\u003c\/p\u003e \u003cp\u003e\u003ci\u003ePhysicochemical and Biomimetic Properties in Drug Discovery\u003c\/i\u003e 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:\u003c\/p\u003e \u003cul\u003e \u003cli\u003eDrug-likeness and the physicochemical property space of known drugs\u003c\/li\u003e \u003cli\u003eBasic pharmacokinetic properties\u003c\/li\u003e \u003cli\u003ePrinciples and methods of chromatography for the application of property measurements\u003c\/li\u003e \u003cli\u003eMolecular physicochemical properties that influence absorption and distribution: lipophilicity, solubility, permeability, and acid dissociation constant (p\u003ci\u003eK\u003c\/i\u003e\u003csub\u003ea\u003c\/sub\u003e)\u003c\/li\u003e \u003cli\u003eModels with measured physicochemical and biomimetic chromatographic descriptors: absorption, distribution, and drug efficiency\u003c\/li\u003e \u003c\/ul\u003e \u003cp\u003eThe final chapter is dedicated to applications and examples of the use of chromatography in drug discovery.\u003c\/p\u003e \u003cp\u003eThroughout 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.\u003c\/p\u003e","brand":"Wiley","offers":[{"title":"Default Title","offer_id":47989789327589,"sku":"NP9781118152126","price":121.0,"currency_code":"USD","in_stock":false}],"thumbnail_url":"\/\/cdn.shopify.com\/s\/files\/1\/1842\/7735\/files\/9781118152126.jpg?v=1761785473","url":"https:\/\/k12savings.com\/es\/products\/physicochemical-and-biomimetic-properties-in-drug-discovery-isbn-9781118152126","provider":"K12savings","version":"1.0","type":"link"}