Drug-like Properties: Concepts, Structure Design and Methods This page intentionally left blank Drug-like Properties: Concepts, Structure Design and Methods: from ADME to Toxicity Optimization Edward H. Kerns and Li Di AMSTERDAM•BOSTON•HEIDELBERG•LONDON NEWYORK•OXFORD•PARIS•SANDIEGO SANFRANCISCO•SINGAPORE•SYDNEY•TOKYO AcademicPressisanimprintofElsevier AcademicPressisanimprintofElsevier 30CorporateDrive,Suite400,Burlington,MA01803,USA 525BStreet,Suite1900,SanDiego,California92101-4495,USA 84Theobald’sRoad,LondonWC1X8RR,UK Thisbookisprintedonacid-freepaper. Copyright©2008,ElsevierInc.Allrightsreserved. Nopartofthispublicationmaybereproducedortransmittedinanyformorbyany means,electronicormechanical,includingphotocopy,recording,oranyinformation storageandretrievalsystem,withoutpermissioninwritingfromthepublisher. PermissionsmaybesoughtdirectlyfromElsevier’sScience&TechnologyRights DepartmentinOxford,UK:phone:(+44)1865843830,fax:(+44)1865853333, E-mail:[email protected] viatheElsevierhomepage(http://elsevier.com),byselecting“Support&Contact” then“CopyrightandPermission”andthen“ObtainingPermissions.” LibraryofCongressCataloging-in-PublicationData Kerns,Edward. Drug-likeproperties:concepts,structuredesign,andmethods:fromADMEto toxicityoptimization/EdwardKernsandLiDi.—1sted. p.;cm. Includesbibliographicalreferencesandindex. ISBN-13:978-0-12-369520-8(alk.paper) 1. Pharmaceuticalchemistry. 2. Drugs—Structure-activityrelationships. 3. Drugdevelopment. 4. Drugs—Design. I. Di,Li. II. Title. [DNLM:1. DrugDesign. 2. DrugEvaluation,Preclinical. 3. DrugToxicity. 4. PharmaceuticalPreparations—metabolism. 5. Pharmacokinetics. 6. Structure-ActivityRelationship.QV744K395d2008] RS420.K472008 615'.19—dc22 2007035586 BritishLibraryCataloguing-in-PublicationData AcataloguerecordforthisbookisavailablefromtheBritishLibrary. ISBN:978-0-1236-9520-8 ForinformationonallAcademicPresspublications visitourWebsiteatwww.books.elsevier.com PrintedintheUnitedStatesofAmerica 07 08 09 10 10 9 8 7 6 5 4 3 2 1 Working together to grow libraries in developing countries www.elsevier.com | www.bookaid.org | www.sabre.org Contents Preface xviii Dedication xx Part 1 Introductory Concepts 1 1 Introduction 3 Problems 5 References 5 2 Advantages of Good Drug-like Properties 6 2.1 Drug-like Properties Are an Integral Part of Drug Discovery 6 2.1.1 Many Properties Are of Interest in Discovery 7 2.1.2 Introduction to the Drug Discovery and Development Process 8 2.1.3 Development Attrition is Reduced by Improving Drug Properties 9 2.1.4 Poor Drug Properties Also Cause Discovery Inefficiencies 9 2.1.5 Marginal Drug Properties Cause Inefficiencies During Development 10 2.1.6 Poor Properties Can Cause Poor Discovery Research 11 2.2 Changing Emphasis on Properties in Discovery 12 2.3 Property Profiling in Discovery 14 2.4 Drug-like Property Optimization in Discovery 15 Problems 15 References 16 3 Barriers to Drug Exposure in Living Systems 17 3.1 Introduction to Barriers 17 3.2 Drug Dosing 18 3.3 Barriers in the Mouth and Stomach 19 3.4 Gastrointestinal Tract Barriers 20 3.4.1 Permeation of the Gastrointestinal Cellular Membrane 22 3.4.2 Passive Diffusion at the Molecular Level 23 3.4.3 Metabolism in the Intestine 24 3.4.4 Enzymatic Hydrolysis in the Intestine 24 3.4.5 Absorption Enhancement in the Intestine 26 3.5 Barriers in the Bloodstream 27 3.5.1 Plasma Enzyme Hydrolysis 27 3.5.2 Plasma Protein Binding 27 3.5.3 Red Blood Cell Binding 28 vi Contents 3.6 Barriers in the Liver 28 3.6.1 Metabolism 29 3.6.2 Biliary Excretion 29 3.7 Barriers in the Kidney 29 3.8 Blood–Tissue Barriers 30 3.9 Tissue Distribution 30 3.10 Consequences of Chirality on Barriers and Properties 31 3.11 Overview of In Vivo Barriers 31 Problems 32 References 33 Part 2 Physicochemical Properties 35 4 Rules for Rapid Property Profiling from Structure 37 4.1 Lipinski Rules 37 4.2 Veber Rules 39 4.3 Other Rules 39 4.4 Application of Rules for Compound Assessment 39 Problems 41 References 42 5 Lipophilicity 43 5.1 Lipophilicity Fundamentals 43 5.2 Lipophilicity Effects 45 5.3 Lipophilicity Case Studies and Structure Modification 46 Problems 47 References 47 6 pK 48 a 6.1 pK Fundamentals 48 a 6.2 pK Effects 50 a 6.3 pK Case Studies 50 a 6.4 Structure Modification Strategies for pK 54 a Problems 54 References 55 7 Solubility 56 7.1 Solubility Fundamentals 57 7.1.1 Solubility Varies with Structure and Physical Conditions 57 7.1.2 Dissolution Rate 57 7.1.3 Structural Properties Affect Solubility 57 7.1.4 Kinetic and Thermodynamic Solubility 60 7.2 Effects of Solubility 62 7.2.1 Low Solubility Limits Absorption and Causes Low Oral Bioavailability 62 7.2.2 Good Solubility is Essential for IV Formulation 63 7.2.3 Acceptance Criteria and Classifications for Solubility 63 7.2.4 Molecular Properties for Solubility and Permeability Often are Opposed 67 Contents vii 7.3 Effects of Physiology on Solubility and Absorption 68 7.3.1 Physiology of the Gastrointestinal Tract 68 7.3.2 Species Differences in Gastrointestinal Tract 68 7.3.3 Food Effect 69 7.4 Structure Modification Strategies to Improve Solubility 70 7.4.1 Add Ionizable Groups 71 7.4.2 Reduce Log P 73 7.4.3 Add Hydrogen Bonding 73 7.4.4 Add Polar Group 74 7.4.5 Reduce Molecular Weight 74 7.4.6 Out-of-Plane Substitution 75 7.4.7 Construct a Prodrug 76 7.5 Strategies for Improving Dissolution Rate 77 7.5.1 Reduce Particle Size 77 7.5.2 Prepare an Oral Solution 78 7.5.3 Formulate with Surfactants 78 7.5.4 Prepare a Salt Form 78 7.6 Salt Form 78 7.6.1 Solubility of Salts 78 7.6.2 Effect of Salt Form on Absorption and Oral Bioavailability 80 7.6.3 Salt Selection 81 7.6.4 Precautions for Using Salt Forms 82 Problems 82 References 84 8 Permeability 86 8.1 Permeability Fundamentals 86 8.1.1 Passive Diffusion Permeability 87 8.1.2 Endocytosis Permeability 89 8.1.3 Active Uptake Permeability 89 8.1.4 Paracellular Permeability 89 8.1.5 Efflux Permeability 89 8.1.6 Combined Permeability 89 8.2 Permeability Effects 90 8.2.1 Effect of Permeability on Bioavailability 90 8.2.2 Effect of Permeability on Cell-Based Activity Assays 91 8.3 Permeability Structure Modification Strategies 92 8.3.1 Ionizable Group to Non-ionizable Group 92 8.3.2 Add Lipophilicity 92 8.3.3 Isosteric Replacement of Polar Groups 93 8.3.4 Esterify Carboxylic Acid 93 8.3.5 Reduce Hydrogen Bonding and Polarity 94 8.3.6 Reduce Size 94 8.3.7 Add Nonpolar Side Chain 96 8.3.8 Prodrug 96 Problems 97 References 98 viii Contents Part 3 Disposition, Metabolism, and Safety 101 9 Transporters 103 9.1 Transporter Fundamentals 103 9.2 Transporter Effects 104 9.2.1 Transporters in Intestinal Epithelial Cells 108 9.2.2 Transporters in Liver Hepatocytes 108 9.2.3 Transporters in Kidney Epithelial Cells 110 9.2.4 Transporters in Blood–Brain Barrier Endothelial Cells 110 9.2.5 Consequences of Chirality on Transporters 110 9.3 Efflux Transporters 111 9.3.1 P-glycoprotein (MDR1, ABCB1) [Efflux] 111 9.3.2 Breast Cancer Resistance Protein (BCRP, ABCG2) [Efflux] 116 9.3.3 Multidrug Resistance Protein 2 (MRP2, ABCC2) [Efflux] 116 9.3.4 Efflux Transporters in the BBB 116 9.4 Uptake Transporters 117 9.4.1 Organic Anion Transporting Polypeptides (OATPs, SLCOs) [Uptake] 117 9.4.2 Di/Tri Peptide Transporters (PEPT1, PEPT2) [Uptake] 117 9.4.3 Organic Anion Transporters (OATs) [Uptake] 118 9.4.4 Organic Cation Transporter (OCT) [Uptake] 118 9.4.5 Large Neutral Amino Acid Transporter (LAT1) [Uptake] 118 9.4.6 Monocarboxylic Acid Transporter (MCT1) [Uptake] 118 9.4.7 Other Uptake Transporters 118 9.4.8 Structure Modification Strategies for Uptake Transporters 119 Problems 119 References 120 10 Blood–Brain Barrier 122 10.1 BBB Fundamentals 123 10.1.1 BBB Permeation Mechanisms 124 10.1.2 Brain Distribution Mechanisms 125 10.1.3 Brain–CSF Barrier 127 10.1.4 Interpreting Data for Brain Penetration 128 10.2 Effects of Brain Penetration 129 10.3 Structure–BBB Penetration Relationships 130 10.4 Structure Modification Strategies to Improve Brain Penetration 131 10.4.1 Reduce Pgp Efflux 132 10.4.2 Reduce Hydrogen Bonds 132 10.4.3 Increase Lipophilicity 133 10.4.4 Reduce MW 133 10.4.5 Replace Carboxylic Acid Groups 133 10.4.6 Add an Intramolecular Hydrogen Bond 133 10.4.7 Modify or Select Structures for Affinity to Uptake Transporters 133 Problems 134 References 135 Contents ix 11 Metabolic Stability 137 11.1 Metabolic Stability Fundamentals 138 11.1.1 Phase I Metabolism 139 11.1.2 Phase II Metabolism 143 11.2 Metabolic Stability Effects 145 11.3 Structure Modification Strategies for Phase I Metabolic Stability 146 11.3.1 Block Metabolic Site By Adding Fluorine 147 11.3.2 Block Metabolic Site By Adding Other Blocking Groups 149 11.3.3 Remove Labile Functional Group 150 11.3.4 Cyclization 151 11.3.5 Change Ring Size 151 11.3.6 Change Chirality 152 11.3.7 Reduce Lipophilicity 152 11.3.8 Replace Unstable Groups 153 11.4 Structure Modification Strategies for Phase II Metabolic Stability 154 11.4.1 Introduce Electron-Withdrawing Groups and Steric Hindrance 154 11.4.2 Change Phenolic Hydroxyl to Cyclic Urea or Thiourea 155 11.4.3 Change Phenolic Hydroxyl to Prodrug 155 11.5 Applications of Metabolic Stability Data 156 11.6 Consequences of Chirality on Metabolic Stability 160 11.7 Substrate Specificity of CYP Isozymes 162 11.7.1 CYP1A2 Substrates 162 11.7.2 CYP2D6 Substrates 163 11.7.3 CYP2C9 Substrates 164 Problems 165 References 167 12 Plasma Stability 169 12.1 Plasma Stability Fundamentals 169 12.1.1 Consequences of Chirality on Plasma Stability 170 12.2 Effects of Plasma Stability 170 12.3 Structure Modification Strategies to Improve Plasma Stability 172 12.3.1 Substitute an Amide for an Ester 172 12.3.2 Increase Steric Hindrance 173 12.3.3 Electron-Withdrawing Groups Decrease Plasma Stability for Antedrug 173 12.4 Applications of Plasma Stability Data 174 12.4.1 Diagnose Poor In Vivo Performance 174 12.4.2 Alert Teams to a Liability 174 12.4.3 Prioritize Compounds for In Vivo Animal Studies 174 12.4.4 Prioritize Synthetic Efforts 175 12.4.5 Screening of Prodrugs 175 12.4.6 Guide Structural Modification 176 Problems 176 References 177 13 Solution Stability 178 13.1 Solution Stability Fundamentals 178 13.2 Effects of Solution Instability 180