ADMET for Medicinal Chemists

KATYA TSAIOUN, PhD, is Chief Scientific Officer of Cyprotex and, previously, president and founder Apredica, which was acquired by Cyprotex. Both companies specialize in the rapid preclinical in vitro assessment of the ADME-Tox (Absorption, Distribution, Metabolism, Elimination, and Toxicity) properties of small-molecule and peptide therapeutics. STEVEN A. KATES, PhD is Vice President of Research and Development at Ischemix. He is a highly experienced chemist with over twenty years in R&D for both life science products and human therapeutics, and has advanced several compounds through drug development from early preclinical to early clinical development. He has more than 100 patents and publications, including one book.

• Preface xvContributors xix1 Introduction 1Corinne Kay1.1 Introduction 11.2 Voyage Through The Digestive System 21.2.1 The Mouth 31.2.2 The Stomach 41.2.3 The Small Intestine: Duodenum 71.2.4 The Small and Large Intestine: Jejunum, Ileum, Colon 91.2.5 Hepatic-Portal Vein 131.3 The Liver Metabolism 151.3.1 CYP450 (CYPs) 171.4 The Kidneys 211.4.1 Active Tubular Secretion 231.4.2 Passive Tubular Reabsorption 241.5 Conclusions 25References 252 In Silico ADME/Tox Predictions 29David Lagorce, Christelle Reynes, Anne-Claude Camproux, Maria A. Miteva, Olivier Sperandio, and Bruno O. Villoutreix2.1 Introduction 292.2 Key Computer Methods for ADME/Tox Predictions 302.2.1 Drug Discovery 302.2.2 Applying or Not ADME/Tox Predictions, Divided Opinions 352.2.3 In Silico ADME/Tox Methods and Modeling Approaches 392.2.4 Physicochemistry, Pharmacokinetics, Drug-Like and Lead-Like Concepts 462.2.5 Lipophilicity 512.2.6 pKa 532.2.7 Transport Proteins 612.2.8 Plasma Protein Binding 622.2.9 Metabolism 652.2.10 Elimination 672.2.11 Toxicity 672.3 Preparation of Compound Collections and Computer Programs, Challenging ADME/Tox Predictions and Statistical Methods 732.3.1 Preparation of Compound Collections and Computer Programs 732.3.2 Preparing a Compound Collection: Materials and Methods 752.3.3 Cleaning and Designing the Compound Collection 832.3.4 Searching for Similarity 852.3.5 Generating 3D Structures 862.4 ADME/Tox Predictions within Pharmaceutics Companies 862.4.1 Actelion Pharmaceuticals Ltd. 862.4.2 Bayer 862.4.3 Bristol-Myers Squibb 872.4.4 Hoffmann-La Roche Ltd. 872.4.5 Neurogen Corporation 872.4.6 Novartis 882.4.7 Schering AG 882.4.8 Vertex Pharmaceuticals 882.5 Challenging ADME/Tox Predictions 882.5.1 Tolcapone 892.5.2 Factor V Inhibitors 892.5.3 CRF-1 Receptor Antagonists 902.6 Statistical Methods 902.6.1 Principal Component Analysis 902.6.2 Partial Least Square 932.6.3 Support Vector Machine 962.6.4 Decision Trees 982.6.5 Neural Networks 1012.7 Conclusions 104References 1053 Absorption and Physicochemical Properties of the NCE 125Jon Selbo and Po-Chang Chiang3.1. Introduction 1253.2. Physicochemical Properties 1263.3. Stability 1273.4. Dissolution and Solubility 1283.4.1. Dissolution Rate, Particle Size, and Solubility 1283.4.2. pH and Salts 1303.4.3. In Vivo Solubilization 1333.5. Solid State 134References 1394 ADME 145Martin E. Dowty, Dean M. Messing, Yurong Lai, and Leonid (Leo) Kirkovsky4.1 Introduction 1454.2 Absorption 1464.2.1 Route of Administration 1464.2.2 Factors Determining Oral Bioavailability 1494.3 Distribution 1574.3.1 Drug Distribution 1574.3.2 Volume of Distribution 1584.3.3 Free Drug Concentration 1604.3.4 CNS Penetration 1624.4 Elimination 1654.4.1 Elimination Versus Clearance 1654.4.2 Metabolism Versus Excretion 1654.4.3 Drug-Free Fraction and Clearance 1664.4.4 Lipophilicity and Clearance 1664.4.5 Transporters and Clearance 1664.4.6 Metabolism 1674.4.7 Excretion 1714.5 Drug Interactions 1744.5.1 Absorption-Driven DDI 1744.5.2 Distribution-Driven DDI 1744.5.3 Excretion-Driven DDI 1744.5.4 Metabolism-Driven DDI 1754.5.5 Tools for Studying Drug Metabolism 1774.5.6 Applications of Drug Metabolism Tools 1804.5.7 Tools for Studying Drug Excretion 1844.6 Strategies for Assessing ADME Properties 1864.6.1 Assessing ADME Attributes at Different Stages of Discovery Projects 1864.7 Tool Summary for Assessing ADME Properties 190References 1905 Pharmacokinetics for Medicinal Chemists 201Leonid (Leo) Kirkovsky and Anup Zutshi5.1 Introduction 2015.1.1 History of Pharmacokinetics as Science 2015.2 ADME 2025.2.1 Absorption 2025.2.2 Distribution 2045.2.3 Metabolism 2075.2.4 Excretion 2075.3 The Mathematics of Pharmacokinetics 2115.3.1 Compartmental Versus Noncompartmental Analysis 2125.4 Drug Administration and PK Observations 2125.4.1 Analysis of Intravenous PK Data 2135.4.2 Analysis of Extravascular PK Data 2275.4.3 Analysis of Intravenous Infusion Data 2305.4.4 Analysis of PK Data after Multiple Dose Administrations 2315.4.5 Analysis of PK Data after Escalating Dose Administrations 2335.5 Human PK Projection 2355.5.1 Allometric Scaling 2355.5.2 Scaling by Physiologically Based Pharmacokinetic Modeling 2375.5.3 In Vitro–In Vivo Correlations 2395.6 PK Practices 2395.6.1 PK Studies for Different Stages of Discovery Projects 2405.6.2 Key Parameters of PK Studies 2415.7 Engineering Molecules with Desired ADME Profile 2695.A Appendices 2695.A.1 General Morphinometric Data for Different Species 2695.A.2 Organ Weights in Different Species 2705.A.3 Organ, Tissue, and Fluid Volumes in Different Species 2715.A.4 Blood Content in Different Rat Organs 2715.A.5 Biofluid Flow through the Organs in Different Species 2725.A.6 Anatomical Characteristics of GI Tract in Different Species 2735.A.7 The pH and Motility of GI Tract in Different Species 2745.A.8 Phase I and Phase II Metabolism in Different Species 274Acknowledgments 277References 2776 Cardiac Toxicity 287Ralf Kettenhofen and Silke Schwengberg6.1 Introduction 2876.2 Ion Channel-Related Cardiac Toxicity 2876.2.1 Cardiac Electrophysiology 2886.2.2 Delayed Repolarization: Mechanisms and Models 2906.2.3 Shortened Ventricular Repolarization 2946.2.4 Alterations in Intracellular Ca2þ Handling 2966.2.5 Preclinical Models for Assessment of Ion Channel-Related Cardiotoxicity 2976.3 Nonarrhythmic Cardiac Toxicity 2996.3.1 Definition of Drug-Induced Cardiac Toxicity 3006.3.2 Assays for Detection of Nonarrhythmic Cardiac Toxicity 3006.3.3 Biochemical and Molecular Basis of Drug-Induced Cardiac Toxicity—Impairment of Mitochondrial Function 304References 3067 Genetic Toxicity: In Vitro Approaches for Medicinal Chemists 315Richard M. Walmsley and David Elder7.1 Introduction 3157.1.1 Scope of this Chapter 3157.1.2 Definitions 3167.1.3 Positive Genotoxicity Data is not Uncommon and Very Costly 3167.1.4 Why Genome Damage is Undesirable 3177.1.5 The Inherent Integrity of the Genome and its Inevitable Corruption 3177.1.6 Many Chemicals can Cause Cancer, but do not Pose a Significant Risk to Humans 3187.1.7 The False Positives: Many Chemicals Produce Positive Genotoxicity Data that are neither Carcinogens nor In Vivo Genotoxins 3187.1.8 Defense Against Genotoxic Damage 3197.1.9 Mechanisms of Genotoxic Damage 3207.1.10 Genotoxicity Assessment Occurs after Medicinal Chemistry Optimization 3217.2 Limitations in the Regulatory In Vitro Genotoxicity Tests 3227.2.1 Biology Limitations of In Vitro Tests 3227.2.2 Hazard and Safety Assessment have Different Requirements 3237.2.3 The Data from Genetic Toxicologists 3237.3 Practical Issues for Genotoxicity Profiling 3247.3.1 Vehicle 3247.3.2 Dilution Range 3247.3.3 Purity 3247.4 Computational Approaches to Genotoxicity Assessment: The In Silico Methods 3257.4.1 General Considerations 3257.4.2 The Chemistry of Genotoxins 3287.5 Genotoxicity Assays for Screening 3357.5.1 Bacterial Gene Mutation Assays 3377.5.2 Mammalian Cell Mutation Assays 3387.5.4 Chromosome Damage and Aberration Assays 3397.5.5 The .Comet. Assay 3407.5.6 DNA Adduct Assessment 3417.5.7 Gene Expression Assays 3417.6 The .Omics. 3437.7 Using Data from In Vitro Profiling: Confirmatory Tests, Follow-Up Tests, and the Link to Safety Assessment and In Vivo Models 3437.7.1 Annotations from Screening Data 3447.7.2 Can a Genetic Toxicity Profile Assist with In Vivo Testing Strategies? 3447.8 What to Test, When, and How 3457.9 Changes to Regulatory Guidelines Can Influence Screening Strategy 3467.10 Summary 347Acknowledgment 347References 3488 Hepatic Toxicity 353Jinghai James Xu and Keith Hoffmaster8.1 Introduction 3538.2 Mechanisms of DILI 3548.2.1 Reactive Metabolite Formation 3558.2.2 Mitochondrial Dysfunction and Oxidative Stress 3578.2.3 Bile Flow, Drug-Induced Cholestasis, and Inhibition of Biliary Efflux Transporters 3598.3 Assays and Test Systems to Measure Various Types of DILI 3608.4 Medicinal Chemistry Strategies to Minimize DILI 3658.5 Future Outlooks 370Acknowledgment 370References 3709 In Vivo Toxicological Considerations 379John P. Devine, Jr.9.1 Introduction 3799.2 Route of Administration 3799.2.1 Oral Route 3809.2.2 Intravenous Route 3819.2.3 Dermal Route 3829.3 Formulation Issues 3839.4 Compound Requirements 3849.5 Animal Models 3859.5.1 Mouse 3859.5.2 Rat 3869.5.3 Dog 3869.5.4 Swine 3869.5.5 Nonhuman Primates 3879.6 IND-Supporting Toxicology Studies 3879.6.1 Single-Dose Studies 3879.6.2 Repeat-Dose Studies 3889.7 Study Result Interpretation 3929.7.1 Clinical Observations 3929.7.2 Body Weight/Feed Consumption 3939.7.3 Clinical Pathology 3939.7.4 Clinical Chemistry 3939.7.5 Electrocardiograms 3949.7.6 Organ Weights 3949.7.7 Pathology 3959.8 Genetic Toxicology Studies 3959.8.1 Gene Mutation 3959.8.2 Chromosomal Aberration 3969.8.3 In Vivo Mouse Micronucleus 3969.9 Conclusion 396References 39710 Preclinical Candidate Nomination and Development 399Nils Bergenhem10.1 Introduction 39910.2 Investigational New Drug Application and Clinical Development 40010.2.1 Chemistry, Manufacturing, and Control Information 40110.2.2 Animal Pharmacology and Toxicology Studies 40110.2.3 Clinical Protocols and Investigator Information 40110.3 Strategic Goals for the Preclinical Development 40210.4 Selection of Preclinical Development Candidate 40310.4.1 Efficacy 40310.4.2 Safety/Tolerance 40510.4.3 PK 40710.4.4 Non-GLP Toxicological Study 40710.5 CMC 40810.5.1 Solubility 40810.5.2 Solutions Stability 40810.5.3 Synthetic Feasibility, Solid-State Stability, and Hygroscopicity 40810.5.4 Patent Position 40810.6 Preclinical Studies 40910.6.1 Example 1: IND Enabling Data Package to Support 1 Month Dosing in Man 41010.6.2 Example 2: Peroxisome Proliferator-Activated Receptor Agonist for Type-2 Diabetes 41010.6.3 Mass Balance 41010.6.4 Animal Pharmacology and Toxicology Studies 41010.6.5 Regulatory 41410.7 Conclusions 415References 41511 Fragment-Based Drug Design: Considerations for Good ADME Properties 417Haitao Ji11.1 Introduction 41711.2 Fragment-Based Screening 41811.2.1 Fragment Library Design 41911.2.2 Detection and Characterization of Weakly Binding Ligands 42011.2.3 Approaches from Fragment to Lead Structures 42711.3 Case Studies of Fragment-Based Screening for Better Bioavailability 43111.3.1 Adenosine Kinase 43111.3.2 Leukocyte Function-Associated Antigen-1 43211.3.3 Matrix Metalloproteinase 3 (Stromelysins) 43211.3.4 Protein Tyrosine Phosphatase 1B 43311.3.5 b-Secretase (BACE-1) 43611.3.6 SH2 Domain of pp60Src [62, 129] 43911.3.7 Thrombin 43911.3.8 Urokinase 44111.3.9 Cathepsin S 44211.3.10 Caspase-3 44211.3.11 HIV-1 Protease 44411.4 De Novo Design 44511.4.1 In Silico Fragment Screening 44711.4.2 Scaffold Hopping 44811.5 Case Studies of De Novo Design for Better Bioavailability 45011.5.1 DNA Gyrase 45011.5.2 Factor Xa 45011.5.3 X-Linked Inhibitor of Apoptosis Protein 45111.5.4 Activator Protein-1 [196b] 45111.6 Minimal Pharmacophoric Elements and Fragment Hopping 45211.6.1 Minimal Pharmacophoric Elements 45211.6.2 Fragment Hopping 45311.6.3 Case Study: Nitric Oxide Synthase 45711.7 Conclusions and Future Perspectives 459Acknowledgments 460References 460Index 487

"The content of the book was overall revealing and if you wanted a general text on ADMET (or ADME) together with a mix of toxicology to complement other texts, then this book would probably be a good addition to your collection." (The British Toxicology Society, 1 May 2011)