The authors describe how properties affect in vivo pharmacological activity and impact in vitro assays. Individual drug-like properties are discussed from a practical point of view, such as solubility, permeability and metabolic stability, with regard to fundamental understanding, applications of property data in drug discovery and examples of structural modifications that have achieved improved property performance. The authors also review various methods for the screening (high throughput), diagnosis (medium throughput) and in-depth (low throughput) analysis of drug properties.
* Serves as an essential working handbook aimed at scientists and students in medicinal chemistry
* Provides practical, step-by-step guidance on property fundamentals, effects, structure-property relationships, and structure modification strategies
* Discusses improvements in pharmacokinetics from a practical chemist's standpoint
Of the thousands of novel compounds that a drug discovery project team invents and that bind to the therapeutic target, typically only a fraction of these have sufficient ADME/Tox properties to become a drug product. Understanding ADME/Tox is critical for all drug researchers, owing to its increasing importance in advancing high quality candidates to clinical studies and the processes of drug discovery. If the properties are weak, the candidate will have a high risk of failure or be less desirable as a drug product. This book is a tool and resource for scientists engaged in, or preparing for, the selection and optimization process. The authors describe how properties affect in vivo pharmacological activity and impact in vitro assays. Individual drug-like properties are discussed from a practical point of view, such as solubility, permeability and metabolic stability, with regard to fundamental understanding, applications of property data in drug discovery and examples of structural modifications that have achieved improved property performance. The authors also review various methods for the screening (high throughput), diagnosis (medium throughput) and in-depth (low throughput) analysis of drug properties. Serves as an essential working handbook aimed at scientists and students in medicinal chemistry Provides practical, step-by-step guidance on property fundamentals, effects, structure-property relationships, and structure modification strategies Discusses improvements in pharmacokinetics from a practical chemist's standpoint
Front Cover 1
Drug-like Properties: Concepts, Structure Design and Methods: from ADME to Toxicity Optimization 4
Copyright Page 5
Table of Contents 6
Preface 19
Dedication 21
Part 1 Introductory Concepts 22
Chapter 1 Introduction 24
Problems 26
References 26
Chapter 2 Advantages of Good Drug-like Properties 27
2.1 Drug-like Properties Are an Integral Part of Drug Discovery 27
2.1.1 Many Properties Are of Interest in Discovery 28
2.1.2 Introduction to the Drug Discovery and Development Process 29
2.1.3 Development Attrition is Reduced by Improving Drug Properties 30
2.1.4 Poor Drug Properties Also Cause Discovery Inefficiencies 30
2.1.5 Marginal Drug Properties Cause Inefficiencies During Development 31
2.1.6 Poor Properties Can Cause Poor Discovery Research 32
2.2 Changing Emphasis on Properties in Discovery 33
2.3 Property Profiling in Discovery 35
2.4 Drug-like Property Optimization in Discovery 36
Problems 36
References 37
Chapter 3 Barriers to Drug Exposure in Living Systems 38
3.1 Introduction to Barriers 38
3.2 Drug Dosing 39
3.3 Barriers in the Mouth and Stomach 40
3.4 Gastrointestinal Tract Barriers 41
3.4.1 Permeation of the Gastrointestinal Cellular Membrane 43
3.4.2 Passive Diffusion at the Molecular Level 44
3.4.3 Metabolism in the Intestine 45
3.4.4 Enzymatic Hydrolysis in the Intestine 45
3.4.5 Absorption Enhancement in the Intestine 47
3.5 Barriers in the Bloodstream 48
3.5.1 Plasma Enzyme Hydrolysis 48
3.5.2 Plasma Protein Binding 48
3.5.3 Red Blood Cell Binding 49
3.6 Barriers in the Liver 49
3.6.1 Metabolism 50
3.6.2 Biliary Excretion 50
3.7 Barriers in the Kidney 50
3.8 Blood–Tissue Barriers 51
3.9 Tissue Distribution 51
3.10 Consequences of Chirality on Barriers and Properties 52
3.11 Overview of In Vivo Barriers 52
Problems 53
References 54
Part 2 Physicochemical Properties 56
Chapter 4 Rules for Rapid Property Profiling from Structure 58
4.1 Lipinski Rules 58
4.2 Veber Rules 60
4.3 Other Rules 60
4.4 Application of Rules for Compound Assessment 60
Problems 62
References 63
Chapter 5 Lipophilicity 64
5.1 Lipophilicity Fundamentals 64
5.2 Lipophilicity Effects 66
5.3 Lipophilicity Case Studies and Structure Modification 67
Problems 68
References 68
Chapter 6 pKa 69
6.1 pKa Fundamentals 69
6.2 pKa Effects 71
6.3 pKa Case Studies 71
6.4 Structure Modification Strategies for pKa 75
Problems 75
References 76
Chapter 7 Solubility 77
7.1 Solubility Fundamentals 78
7.1.1 Solubility Varies with Structure and Physical Conditions 78
7.1.2 Dissolution Rate 78
7.1.3 Structural Properties Affect Solubility 78
7.1.4 Kinetic and Thermodynamic Solubility 81
7.2 Effects of Solubility 83
7.2.1 Low Solubility Limits Absorption and Causes Low Oral Bioavailability 83
7.2.2 Good Solubility is Essential for IV Formulation 84
7.2.3 Acceptance Criteria and Classifications for Solubility 84
7.2.4 Molecular Properties for Solubility and Permeability Often are Opposed 88
7.3 Effects of Physiology on Solubility and Absorption 89
7.3.1 Physiology of the Gastrointestinal Tract 89
7.3.2 Species Differences in Gastrointestinal Tract 89
7.3.3 Food Effect 90
7.4 Structure Modification Strategies to Improve Solubility 91
7.4.1 Add Ionizable Groups 92
7.4.2 Reduce Log P 94
7.4.3 Add Hydrogen Bonding 94
7.4.4 Add Polar Group 95
7.4.5 Reduce Molecular Weight 95
7.4.6 Out-of-Plane Substitution 96
7.4.7 Construct a Prodrug 97
7.5 Strategies for Improving Dissolution Rate 98
7.5.1 Reduce Particle Size 98
7.5.2 Prepare an Oral Solution 99
7.5.3 Formulate with Surfactants 99
7.5.4 Prepare a Salt Form 99
7.6 Salt Form 99
7.6.1 Solubility of Salts 99
7.6.2 Effect of Salt Form on Absorption and Oral Bioavailability 101
7.6.3 Salt Selection 102
7.6.4 Precautions for Using Salt Forms 103
Problems 103
References 105
Chapter 8 Permeability 107
8.1 Permeability Fundamentals 107
8.1.1 Passive Diffusion Permeability 108
8.1.2 Endocytosis Permeability 110
8.1.3 Active Uptake Permeability 110
8.1.4 Paracellular Permeability 110
8.1.5 Efflux Permeability 110
8.1.6 Combined Permeability 110
8.2 Permeability Effects 111
8.2.1 Effect of Permeability on Bioavailability 111
8.2.2 Effect of Permeability on Cell-Based Activity Assays 112
8.3 Permeability Structure Modification Strategies 113
8.3.1 Ionizable Group to Non-ionizable Group 113
8.3.2 Add Lipophilicity 113
8.3.3 Isosteric Replacement of Polar Groups 114
8.3.4 Esterify Carboxylic Acid 114
8.3.5 Reduce Hydrogen Bonding and Polarity 115
8.3.6 Reduce Size 115
8.3.7 Add Nonpolar Side Chain 117
8.3.8 Prodrug 117
Problems 118
References 119
Part 3 Disposition, Metabolism, and Safety 122
Chapter 9 Transporters 124
9.1 Transporter Fundamentals 124
9.2 Transporter Effects 125
9.2.1 Transporters in Intestinal Epithelial Cells 129
9.2.2 Transporters in Liver Hepatocytes 129
9.2.3 Transporters in Kidney Epithelial Cells 131
9.2.4 Transporters in Blood–Brain Barrier Endothelial Cells 131
9.2.5 Consequences of Chirality on Transporters 131
9.3 Efflux Transporters 132
9.3.1 P-glycoprotein (MDR1, ABCB1) [Efflux] 132
9.3.2 Breast Cancer Resistance Protein (BCRP, ABCG2) [Efflux] 137
9.3.3 Multidrug Resistance Protein 2 (MRP2, ABCC2) [Efflux] 137
9.3.4 Efflux Transporters in the BBB 137
9.4 Uptake Transporters 138
9.4.1 Organic Anion Transporting Polypeptides (OATPs, SLCOs) [Uptake] 138
9.4.2 Di/Tri Peptide Transporters (PEPT1, PEPT2) [Uptake] 138
9.4.3 Organic Anion Transporters (OATs) [Uptake] 139
9.4.4 Organic Cation Transporter (OCT) [Uptake] 139
9.4.5 Large Neutral Amino Acid Transporter (LAT1) [Uptake] 139
9.4.6 Monocarboxylic Acid Transporter (MCT1) [Uptake] 139
9.4.7 Other Uptake Transporters 139
9.4.8 Structure Modification Strategies for Uptake Transporters 140
Problems 140
References 141
Chapter 10 Blood–Brain Barrier 143
10.1 BBB Fundamentals 144
10.1.1 BBB Permeation Mechanisms 145
10.1.2 Brain Distribution Mechanisms 146
10.1.3 Brain–CSF Barrier 148
10.1.4 Interpreting Data for Brain Penetration 149
10.2 Effects of Brain Penetration 150
10.3 Structure–BBB Penetration Relationships 151
10.4 Structure Modification Strategies to Improve Brain Penetration 152
10.4.1 Reduce Pgp Efflux 153
10.4.2 Reduce Hydrogen Bonds 153
10.4.3 Increase Lipophilicity 154
10.4.4 Reduce MW 154
10.4.5 Replace Carboxylic Acid Groups 154
10.4.6 Add an Intramolecular Hydrogen Bond 154
10.4.7 Modify or Select Structures for Affinity to Uptake Transporters 154
Problems 155
References 156
Chapter 11 Metabolic Stability 158
11.1 Metabolic Stability Fundamentals 159
11.1.1 Phase I Metabolism 160
11.1.2 Phase II Metabolism 164
11.2 Metabolic Stability Effects 166
11.3 Structure Modification Strategies for Phase I Metabolic Stability 167
11.3.1 Block Metabolic Site By Adding Fluorine 168
11.3.2 Block Metabolic Site By Adding Other Blocking Groups 170
11.3.3 Remove Labile Functional Group 171
11.3.4 Cyclization 172
11.3.5 Change Ring Size 172
11.3.6 Change Chirality 173
11.3.7 Reduce Lipophilicity 173
11.3.8 Replace Unstable Groups 174
11.4 Structure Modification Strategies for Phase II Metabolic Stability 175
11.4.1 Introduce Electron-Withdrawing Groups and Steric Hindrance 175
11.4.2 Change Phenolic Hydroxyl to Cyclic Urea or Thiourea 176
11.4.3 Change Phenolic Hydroxyl to Prodrug 176
11.5 Applications of Metabolic Stability Data 177
11.6 Consequences of Chirality on Metabolic Stability 181
11.7 Substrate Specificity of CYP Isozymes 183
11.7.1 CYP1A2 Substrates 183
11.7.2 CYP2D6 Substrates 184
11.7.3 CYP2C9 Substrates 185
Problems 186
References 188
Chapter 12 Plasma Stability 190
12.1 Plasma Stability Fundamentals 190
12.1.1 Consequences of Chirality on Plasma Stability 191
12.2 Effects of Plasma Stability 191
12.3 Structure Modification Strategies to Improve Plasma Stability 193
12.3.1 Substitute an Amide for an Ester 193
12.3.2 Increase Steric Hindrance 194
12.3.3 Electron-Withdrawing Groups Decrease Plasma Stability for Antedrug 194
12.4 Applications of Plasma Stability Data 195
12.4.1 Diagnose Poor In Vivo Performance 195
12.4.2 Alert Teams to a Liability 195
12.4.3 Prioritize Compounds for In Vivo Animal Studies 195
12.4.4 Prioritize Synthetic Efforts 196
12.4.5 Screening of Prodrugs 196
12.4.6 Guide Structural Modification 197
Problems 197
References 198
Chapter 13 Solution Stability 199
13.1 Solution Stability Fundamentals 199
13.2 Effects of Solution Instability 201
13.3 Structure Modification Strategies to Improve Solution Stability 201
13.3.1 Eliminate or Modify the Unstable Group 201
13.3.2 Add an Electron-Withdrawing Group 202
13.3.3 Isosteric Replacement of Labile Functional Group 203
13.3.4 Increase Steric Hindrance 203
13.4 Applications of Solution Stability Data 204
Problems 206
References 206
Chapter 14 Plasma Protein Binding 208
14.1 Plasma Protein Binding Fundamentals 208
14.1.1 Consequences of Chirality on PPB 210
14.2 PPB Effects 211
14.2.1 Impact of PPB on Distribution 212
14.2.2 Effect of PPB on Clearance 213
14.2.3 Effect of PPB on Pharmacology 213
14.3 PPB Case Studies 214
14.4 Structure Modification Strategies for PPB 214
14.5 Strategy for PPB in Discovery 215
14.6 Red Blood Cell Binding 215
Problems 215
References 216
Chapter 15 Cytochrome P450 Inhibition 218
15.1 CYP Inhibition Fundamentals 218
15.2 Effects of CYP Inhibition 220
15.3 CYP Inhibition Case Studies 222
15.3.1 Consequences of Chirality on CYP Inhibition 223
15.4 Structure Modification Strategies to Reduce CYP Inhibition 224
15.5 Reversible and Irreversible CYP Inhibition 225
15.6 Other DDI Issues 226
15.6.1 Candidate as Victim to a Metabolism Inhibition Perpetrator 226
15.6.2 Candidate as a Victim or Perpetrator at a Transporter 227
15.6.3 Candidate as a Victim or Perpetrator of Metabolic Enzyme Induction 227
Problems 227
References 228
Chapter 16 hERG Blocking 230
16.1 hERG Fundamentals 230
16.2 hERG Blocking Effects 232
16.3 hERG Blocking Structure–Activity Relationship 233
16.4 Structure Modification Strategies for hERG 234
Problems 234
References 235
Additional Reading 235
Chapter 17 Toxicity 236
17.1 Toxicity Fundamentals 237
17.1.1 Toxicity Terms and Mechanisms 238
17.1.2 Toxicity Mechanisms 238
17.2 Toxicity Case Studies 242
17.3 Structure Modification Strategies to Improve Safety 243
Problems 243
References 244
Chapter 18 Integrity and Purity 245
18.1 Fundamentals of Integrity and Purity 245
18.2 Integrity and Purity Effects 245
18.3 Applications of Integrity and Purity 247
18.3.1 Case Study 247
Problems 248
References 248
Chapter 19 Pharmacokinetics 249
19.1 Introduction to Pharmacokinetics 249
19.2 PK Parameters 250
19.2.1 Volume of Distribution 250
19.2.2 Area Under the Curve 252
19.2.3 Clearance 252
19.2.4 Half-life 254
19.2.5 Bioavailability 255
19.3 Effects of Plasma Protein Binding on PK Parameters 255
19.4 Tissue Uptake 255
19.5 Using PK Data in Drug Discovery 256
Problems 261
References 262
Chapter 20 Lead-like Compounds 263
20.1 Lead-likeness 263
20.2 Template Conservation 265
20.3 Triage 266
20.4 Fragment-Based Screening 266
20.5 Lead-like Compounds Conclusions 268
Problems 268
References 269
Chapter 21 Strategies for Integrating Drug-like Properties into Drug Discovery 270
21.1 Assess Drug-like Properties Early 270
21.2 Rapidly Assess Drug-like Properties for All New Compounds 271
21.3 Develop Structure–Property Relationships 271
21.4 Iterative Parallel Optimization 272
21.5 Obtain Property Data that Relates Directly to Structure 272
21.6 Apply Property Data to Improve Biological Experiments 273
21.7 Utilize Customized Assays to Answer Specific Project Questions 273
21.8 Diagnose Inadequate Performance in Complex Systems Using Individual Properties 273
Problems 274
References 274
Part 4 Methods 276
Chapter 22 Methods for Profiling Drug-like Properties: General Concepts 278
22.1 Property Data Should be Rapidly Available 278
22.2 Use Relevant Assay Conditions 278
22.3 Evaluate the Cost-to-Benefit Ratio for Assays 278
22.4 Choose an Ensemble of Key Properties to Evaluate 279
22.5 Use Well-Developed Assays 280
Problems 280
References 280
Chapter 23 Lipophilicity Methods 281
23.1 In Silico Lipophilicity Methods 281
23.2 Experimental Lipophilicity Methods 285
23.2.1 Scaled-Down Shake Flask Method for Lipophilicity 286
23.2.2 Reversed-Phase HPLC Method for Lipophilicity 287
23.2.3 Capillary Electrophoresis Method for Lipophilicity 288
23.3 In-Depth Lipophilicity Methods 288
23.3.1 Shake Flask Method for Lipophilicity 288
23.3.2 pH-Metric Method for Lipophilicity 289
Problems 289
References 290
Chapter 24 pKa Methods 292
24.1 In Silico pKa Methods 292
24.2 Experimental pKa Methods 294
24.2.1 Spectral Gradient Analysis Method for pKa 294
24.2.2 Capillary Electrophoresis Method for pKa 294
24.3 In-Depth pKa Method: pH-Metric 295
Problems 296
References 296
Chapter 25 Solubility Methods 297
25.1 Literature Solubility Calculation Methods 297
25.2 Commercial Software for Solubility 298
25.3 Kinetic Solubility Methods 299
25.3.1 Direct UV Kinetic Solubility Method 299
25.3.2 Nephelometric Kinetic Solubility Method 301
25.3.3 Turbidimetric In Vitro Solubility Method 302
25.3.4 Customized Kinetic Solubility Method 303
25.4 Thermodynamic Solubility Methods 304
25.4.1 Equilibrium Shake Flask Thermodynamic Solubility Method 304
25.4.2 Potentiometric In Vitro Thermodynamic Solubility Method 304
25.4.3 Thermodynamic Solubility in Various Solvents 305
Problems 306
References 306
Chapter 26 Permeability Methods 308
26.1 In Silico Permeability Methods 308
26.2 In Vitro Permeability Methods 309
26.2.1 IAM HPLC 309
26.2.2 Cell Layer Method for Permeability 309
26.2.3 Artificial Membrane Permeability Assay 313
26.2.4 Comparison of Caco-2 and PAMPA Methods 314
26.3 In Depth Permeability Methods 315
Problems 316
References 317
Chapter 27 Transporter Methods 320
27.1 In Silico Transporter Methods 320
27.2 In Vitro Transporter Methods 321
27.2.1 Cell Layer Permeability Methods for Transporters 321
27.2.2 Uptake Method for Transporters 325
27.2.3 Oocyte Uptake Method for Transporters 325
27.2.4 Inverted Vesicle Assay for Transporters 326
27.2.5 ATPase Assay for ATP Binding Cassette Transporters 326
27.2.6 Calcein AM Assay for Pgp Inhibitor 327
27.3 In Vivo Methods for Transporters 328
27.3.1 Genetic Knockout Animal Experiments for Transporters 328
27.3.2 Chemical Knockout Experiments for Transporters 328
Problems 329
References 329
Chapter 28 Blood–Brain Barrier Methods 332
28.1 In Silico Methods for BBB 333
28.1.1 Classification Models 333
28.1.2 Quantitative Structure–Activity Relationship Methods 333
28.1.3 Commercial Software 334
28.2 In Vitro Methods for BBB 335
28.2.1 Physicochemical Methods for BBB 335
28.2.2 Cell-based In Vitro Methods [BBB Permeability] 338
28.3 In Vivo Methods for BBB 340
28.3.1 B/P Ratio or Log BB [Brain Distribution] 340
28.3.2 Brain Uptake Index [BBB Permeability] 341
28.3.3 In Situ Perfusion [BBB Permeability, Log PS, µL/min/g] 342
28.3.4 Mouse Brain Uptake Assay [BBB Permeability and Brain Distribution] 343
28.3.5 Microdialysis Method for BBB 344
28.3.6 Cerebrospinal Fluid Method for BBB 345
28.4 Assessment Strategy for Brain Penetration 345
Problems 346
References 346
Chapter 29 Metabolic Stability Methods 350
29.1 In Silico Metabolic Stability Methods 352
29.2 In Vitro Metabolic Stability Methods 352
29.2.1 General Aspects of Metabolic Stability Methods 352
29.2.2 In Vitro Microsomal Assay for Metabolic Stability 356
29.2.3 In Vitro S9 Assay for Metabolic Stability 359
29.2.4 In Vitro Hepatocytes Assay for Metabolic Stability 361
29.2.5 In Vitro Phase II Assay for Metabolic Stability 361
29.2.6 Metabolic Phenotyping 362
29.2.7 In Vitro Metabolite Structure Identification 363
Problems 366
References 367
Chapter 30 Plasma Stability Methods 369
Problems 372
References 372
Chapter 31 Solution Stability Methods 374
31.1 General Method for Solution Stability Assays 374
31.2 Method for Solution Stability in Biological Assay Media 376
31.3 Methods for pH Solution Stability 377
31.4 Methods for Solution Stability in Simulated Gastrointestinal Fluids 377
31.5 Identification of Degradation Products from Solution Stability Assays 378
31.6 In-Depth Solution Stability Methods for Late Stages of Drug Discovery 378
Problems 379
References 379
Chapter 32 CYP Inhibition Methods 381
32.1 In Silico CYP Inhibition Methods 381
32.2 In Vitro CYP Inhibition Methods 382
32.2.1 Fluorescent Assay for CYP Inhibition 385
32.2.2 Single Substrate HLM Assay for CYP Inhibition 386
32.2.3 Cocktail Substrate HLM Assay for CYP Inhibition 386
32.2.4 Double Cocktail Assay for CYP Inhibition 388
32.3 CYP Inhibition Assessment Strategy 388
Problems 389
References 389
Chapter 33 Plasma Protein Binding Methods 393
33.1 In Silico PPB Methods 393
33.1.1 Literature In Silico PPB Methods 393
33.1.2 Commercial In Silico PPB Methods 393
33.2 In Vitro PPB Methods 394
33.2.1 Equilibrium Dialysis Method 394
33.2.2 Ultrafiltration Method 395
33.2.3 Ultracentrifugation Method 396
33.2.4 Immobilized Protein High-Performance Liquid Chromatography Column Method 396
33.2.5 Microdialysis Method 396
33.2.6 Other PPB Methods 397
33.3 Red Blood Cell Binding 397
Problems 397
References 398
Chapter 34 hERG Methods 399
34.1 In Silico hERG Methods 400
34.2 In Vitro hERG Methods 400
34.2.1 Membrane Potential–Sensitive Dye Method for hERG 400
34.2.2 Ligand Binding Method for hERG 402
34.2.3 Rubidium Efflux Method for hERG 402
34.2.4 Patch-Clamp Method for hERG 402
34.2.5 High-Throughput Patch-Clamp Method for hERG 404
34.3 In Vivo hERG Methods 405
Problems 405
References 406
Chapter 35 Toxicity Methods 407
35.1 In Silico Toxicity Methods 408
35.1.1 Knowledge-Based Expert System In Silico Toxicity Methods 408
35.1.2 Statistically Based In Silico Toxicity Methods 409
35.2 In Vitro Toxicity Assays 409
35.2.1 Drug–Drug Interaction 409
35.2.2 hERG Block Assays 410
35.2.3 Mutagenicity/Genotoxicity 410
35.2.4 Cytotoxicity 412
35.2.5 Teratogenicity: Zebrafish Model 413
35.2.6 Selectivity Screens 413
35.2.7 Reactivity Screens 414
35.3 In Vivo Toxicity 414
35.3.1 Discovery In Vivo Toxicity 414
35.3.2 Preclinical and Clinical In Vivo Toxicity 414
35.3.3 Biomarkers of In Vivo Toxic Responses 416
Problems 417
References 417
Chapter 36 Integrity and Purity Methods 420
36.1 Criteria for Integrity and Purity Assays 420
36.2 Samples for Integrity and Purity Profiling 421
36.3 Requirements of Integrity and Purity Profiling Methods 422
36.4 Integrity and Purity Method Advice 422
36.4.1 Sample Preparation 423
36.4.2 Component Separation 423
36.4.3 Quantitation 424
36.4.4 Identity Characterization 425
36.5 Follow-up on Negative Identity Results 426
36.6 Example Method 426
36.7 Method Case Studies 427
Problems 428
References 428
Chapter 37 Pharmacokinetic Methods 430
37.1 PK Dosing 430
37.1.1 Single-Compound Dosing 430
37.1.2 Cassette Dosing 430
37.2 PK Sampling and Sample Preparation 431
37.3 Instrumental Analysis 432
37.4 Example Pharmacokinetic Data 433
37.5 Tissue Uptake 434
Problems 435
References 435
Part 5 Specific Topics 438
Chapter 38 Diagnosing and Improving Pharmacokinetic Performance 440
38.1 Diagnosing Underlying Property Limitations from PK Performance 441
38.1.1 High Clearance After IV Injection 441
38.1.2 Low Oral Bioavailability 442
38.2 Case Studies on Interpreting Unusual PK Performance 442
38.2.1 PK of CCR5 Antagonist UK-427,857 442
38.2.2 PK of Triazole Antifungal Voriconazole 443
Problems 445
References 445
Chapter 39 Prodrugs 447
39.1 Using Prodrugs to Improve Solubility 449
39.2 Prodrugs to Increase Passive Permeability 451
39.2.1 Ester Prodrugs for Carboxylic Acids 452
39.2.2 Ester Prodrugs for Alcohols and Phenols 453
39.2.3 Prodrugs Derived from Nitrogen-Containing Functional Group 454
39.3 Transporter-Mediated Prodrugs to Enhance Intestinal Absorption 455
39.4 Prodrugs to Reduce Metabolism 456
39.5 Prodrugs to Target Specific Tissues 457
39.6 Soft Drugs 458
Problems 458
References 459
Chapter 40 Effects of Properties on Biological Assays 460
40.1 Effects of Insolubility in DMSO 462
40.2 Dealing with Insolubility in DMSO 464
40.3 Effects of Insolubility in Aqueous Buffers 464
40.4 Dealing with Insolubility in Aqueous Buffers 466
40.4.1 Modify the Dilution Protocol to Keep Compounds in Solution 466
40.4.2 Assess Compound Solubility and Concentrations 467
40.4.3 Optimize Assays for Low Solubility Compounds 468
40.4.4 Effects of Permeability in Cell-Based Assays 469
40.4.5 Dealing with Permeability in Cell-Based Assays 469
40.4.6 Effects of Chemical Instability in Bioassays 469
40.4.7 Dealing with Chemical Instability in Bioassays 470
Problems 470
References 471
Chapter 41 Formulation 474
41.1 Routes of Administration 475
41.2 Potency Drives Delivery Opportunities 476
41.3 Formulation Strategies 477
41.4 Practical Guide for Formulation in Drug Discovery 483
41.4.1 Formulation for PK Studies 484
41.4.2 Formulation for Toxicity Studies 485
41.4.3 Formulation for Pharmacological Activity Studies 485
Problems 486
References 486
Appendix I Answers to Chapter Problems 489
Appendix II General References 513
Appendix III Glossary 514
Index 535
Color Plates 548
Chapter 2 Advantages of Good Drug-like Properties
Overview
2.1 Drug-like Properties Are an Integral Part of Drug Discovery
Drug discovery is continuously advancing as new fundamental knowledge, methods, technologies, and strategies are introduced. These new capabilities result in changes in the discovery process. For example:
Drug discovery is constantly reevaluating itself in order to advance in speed, efficiency, and quality and thus remain successful.
Drug-like property optimization is another area of drug discovery advancement. It offers significant opportunities for enhancing discovery success. This book focuses on the fundamental knowledge, methods, and strategies of absorption, distribution, metabolism, excretion, and toxicity (ADME/Tox) and how structures can be optimized. As background for this information, this chapter describes how optimization of ADME/Tox has progressed.
The term drug-like captures the concept that certain properties of compounds are most advantageous in their becoming successful drug products. The term became commonly used following the pivotal work of Lipinski and colleagues.[1] Their work examined the structural properties that affect the physicochemical properties of solubility and permeability and their effect on drug absorption. Since that article, the term drug-like properties has expanded and been linked with all properties that affect ADME/Tox.
2.1.1 Many Properties Are of Interest in Discovery
Drug-like properties are an integral element of drug discovery projects. Properties of interest to discovery scientists include the following:
The structure determines the compound’s properties (Figure 2.1). When these structural properties interact with the physical environment, they cause physicochemical properties (e.g., solubility). When these structural properties interact with proteins, they cause biochemical properties (e.g., metabolism). At the highest level, when the physicochemical and biochemical properties interact with living systems they cause PK and toxicity. Medicinal chemists control the PK and toxicity properties of the compound by modifying the structure.
Figure 2.1 Compound structure determines the fundamental properties that determine physicochemical and biochemical properties, which ultimately determine pharmacokinetics and toxicity.
2.1.2 Introduction to the Drug Discovery and Development Process
Before exploring how properties affect drug candidates, it is useful to briefly review the process of drug discovery and development. New drug candidates are found during the discovery stage (Figure 2.2). They then enter clinical development and, if approved by the Food and Drug Administration (FDA), become drug products that are used in patient therapy. The major activities in each stage are listed in Figure 2.2. This book focuses on the discovery stage. However, the later stages impose stringent drug-like requirements on the properties of candidates. Thus, it is necessary to anticipate these requirements during drug discovery and promote to development only those compounds that have the highest chances of success.
Figure 2.2 Overview of drug research and development stages and their major activities.
Drug discovery is diagramed in greater detail in Figure 2.3. In general, successive stages involve increasing depth of study and more stringent advancement criteria. The discovery screening process initially casts a broad net, to explore diverse pharmacophore structural space. It then narrows these possibilities to select a few lead scaffolds (templates). These are structurally modified to explore SARs, the cornerstone of modern drug discovery, during the lead optimization stage. Finally, candidates for development are subjected to in-depth studies to qualify or disqualify them for development.
Figure 2.3 Stages of drug discovery, primary goals, and major activities.
2.1.3 Development Attrition is Reduced by Improving Drug Properties
Much of the early history of drug discovery focused on finding active compounds. Issues such as PK, toxicity, solubility, and stability were addressed during the development phase. In 1988 a pivotal paper on the reasons for failure of drugs in development revealed a startling problem.[2] Approximately 39% of drugs were failing in development because of poor biopharmaceutical properties (PK and bioavailability). With the high cost of development, this failure represented a major economic loss for the companies. Furthermore, years of work on discovery and development were lost, and the introduction of a new drug product was delayed.
This great need for enhancement was actively addressed by adding resources to assess biopharmaceutical properties during late discovery. Sorting out the compounds with acceptable properties at this stage did not require the rigorous methods applied during development. Thus, for this task, methods used during development were adapted to use fewer resources and to operate at higher throughput. Criteria were relaxed to reflect the reduced accuracy and precision of the revised methods and the lower level of detail needed for decisions at this stage. The assessment of PK was implemented in the late-discovery/predevelopment stage. This testing succeeded in keeping poor candidates from progressing into development and reduced development attrition.
2.1.4 Poor Drug Properties Also Cause Discovery Inefficiencies
Once late-discovery biopharmaceutical assessment was in place and an attrition burden was lifted from development, another discovery need was revealed. Candidates that were failing in late discovery because of poor properties still caused a great burden on drug discovery. Failure late in discovery meant that the project to discover a new drug had lost valuable time and resources on the failed candidate and had to start over. This recognition led to the implementation of property assessment even earlier in discovery so that such losses would be reduced. In pharmaceutical companies, implementation has been accomplished by different approaches. In one approach, higher-throughput animal PK capabilities are added earlier in discovery in order to screen more compounds in vivo for PK. This strategy measures the key PK properties that can predict in vivo candidate ADME success. In a second strategy, higher-throughput in vitro property assays are used. These assays measure fundamental physicochemical and biochemical properties, such as solubility, permeability, and metabolic stability, which determine higher-level properties, such as PK. In vitro studies require fewer resources and animals per compound than do PK studies, so more compounds can be assessed using in vitro assays. Also, physicochemical and biochemical properties, determined with in vitro methods, can be more useful to medicinal chemists in deciding how to modify structures to improve properties.[3–5] Medicinal chemists can correlate physicochemical and biochemical properties with structural features more closely than with PK properties. Physicochemical and biochemical methods typically measure a single property (e.g., passive diffusion permeability). On the other hand, PK properties result from multiple variables operating in a dynamic manner, and they do not indicate which discrete structural modifications to make. Most pharmaceutical companies use a combination of these two strategies during discovery.
As a result of these enhancements of discovery, the property-induced failure of compounds in development declined dramatically from 39% in 1988 to 10% in 2000.[6] Figure 2.4 shows that pharmaceutical companies have been...
| Erscheint lt. Verlag | 26.7.2010 |
|---|---|
| Sprache | englisch |
| Themenwelt | Sachbuch/Ratgeber |
| Medizin / Pharmazie ► Gesundheitsfachberufe | |
| Medizin / Pharmazie ► Medizinische Fachgebiete ► Pharmakologie / Pharmakotherapie | |
| Naturwissenschaften ► Biologie ► Biochemie | |
| Naturwissenschaften ► Chemie ► Organische Chemie | |
| Technik | |
| ISBN-10 | 0-08-055761-9 / 0080557619 |
| ISBN-13 | 978-0-08-055761-8 / 9780080557618 |
| Haben Sie eine Frage zum Produkt? |
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