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Pharmacokinetic profiling in drug research: biological, physicochemical, and computational strategies

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Informatics and robotics are the workhorses of a technological revolution in drug research. On them are based combinatorial chemistry, which yields compounds by the many thousands, and high-throughput bioassays, which screen them for activity. The results are avalanches of 'hits', which invade the databases like swarms of locusts. But far from being a plague, these innumerable compounds become a blessing if properly screened for 'drugability', i.e., for 'drug-like' properties such as good pharmacokinetic (PK) behavior. Pharmacokinetic profiling of bioactive compounds has, thus, become a sine qua non condition for cherry-picking the most promising hits. Just as important, but less visible, are the structure-property and structure-ADME relations, which emerge from PK profiling and provide useful feedback when designing new synthetic series. As a result, the screening, design, and optimization of pharmacokinetic properties has become the bottleneck and a major challenge in drug research. To shorten the time-consuming development and high rate of attrition of active compounds ultimately doomed by hidden pharmacokinetic defects, powerful biological, physicochemical, and computational approaches are being developed, whose objectives are to increase the clinical relevance of drug design and to eliminate as soon as possible compounds with unfavorable physicochemical properties and pharmacokinetic profiles.

The profiling of ADME properties (absorption, distribution, metabolism, and excretion) is the topic of this book. Following the extraordinary success of the previous work ('Pharmacokinetic Optimization in Drug Research: Biological, Physicochemical, and Computational Strategies', Eds. B. Testa, H. van de Waterbeemd, G. Volkers, R. Guy, Verlag Helvetica Chimica Acta, Z? 2001, 655 pages), there was a need for an essentially new edition focusing on the latest theoretical and technological breakthroughs. In this unique work, international authorities and practicing experts from academia and industry offer state-of-the-art presentations of concepts, methods and technologies now in use or development in drug research. The biological strategies emphasized in the book include cell cultures, drug-metabolizing enzymes, transporters and plasma protein binding. The physicochemical strategies focus on artificial membrane-permeability assays, on solubility and lipophilicity and related molecular properties as factors and predictors of pharmacokinetic behavior, and on stability and solid-state properties. Computational strategies comprize the exploration of property spaces, pharmacophore searching to predict biotransformation and enzyme inhibition, and expert systems to process biopharmaceutical profiling data.

In addition to its 28 chapters, the book includes a CD-ROM containing the invited lectures, oral communications, and posters (in full version) presented at the Third LogP Symposium, 'Physicochemical and Biological Profiling in Drug Research', held at the Federal Institute of Technology (ETH) of Z?in March 2004.

Author(s): Bernard Testa, Stefanie D. Krämer, Heidi Wunderli-Allenspach, Gerd Folkers
Publisher: Wiley-VCH
Year: 2006

Language: English
Commentary: Conference publication
Pages: 505
City: ZuМ€rich Verl. Helvetica Chimica Acta u.a

Cover Page......Page 1
Title Page......Page 3
ISBN 3906390357......Page 4
Preface......Page 5
Part II. Biological Strategies......Page 8
Part III. Physicochemical Strategies......Page 9
Part IV. Computational Strategies......Page 10
Part V. Concluding Chapters......Page 11
Sponsors......Page 12
Part I. Setting the Scene......Page 13
1. Introduction......Page 15
2. The Drug Discovery Process......Page 17
3. The Shape of Things to Come......Page 22
4. Balancing the Promises and the Problems......Page 23
5. For Whom, for What?......Page 26
6. Science and the Social Order......Page 29
7. Conclusions......Page 32
1. Introduction......Page 37
2. Lead-Like and Drug-Like Properties......Page 38
3. Structure-Based and Property-Based Drug Design......Page 39
5. In vitro Physicochemical and ADME Profiling......Page 40
6. Conclusions:Towards the in combo Strategy - Combination of in silico and in vitro Screening Technologies......Page 53
Part II. Biological Strategies......Page 59
2. Transverse and Lateral Structure of Lipid Bilayers......Page 61
3. Permeability and Adsorption Properties of Lipid Bilayers......Page 67
4. Lipids Sense for Curvature......Page 71
5. Acylated Peptides at Membranes......Page 73
6. The Magic Bullet Revisited......Page 75
7. Conclusions......Page 81
1. Introduction......Page 83
2. Alternative Models......Page 84
3. Transcellular and Paracellular Drug Transport Pathways......Page 85
4. Comparative Studies......Page 86
5. Conclusions......Page 89
1. Introduction......Page 91
2. Integration of Mass Spectrometry in Metabolic Studies......Page 93
3. Metabolic Studies: Major Advances in Development......Page 96
4. Metabolic Studies: Impact on Research Programs......Page 102
5. Conclusions......Page 103
1. Introduction......Page 105
2. In vitro Assays......Page 108
3. Cell Culture Systems and Liver Slices......Page 110
4. Animal Models and Other in vivo Techniques......Page 111
5. In silico Approaches......Page 112
6. Conclusions......Page 113
1. Introduction......Page 117
2. Transport of Organic Anions in the Liver and Kidney......Page 118
3. Conclusions......Page 127
1. Introduction......Page 131
2. Experimental Aspects......Page 133
3. Biological Aspects......Page 136
4. The Importance of Plasma Protein Binding in Drug Metabolism and Pharmacokinetic Profiling......Page 140
5. Drug–Drug and Disease–Drug Interactions......Page 145
6. Quantitative Structure–Property Relationships in Plasma Protein Binding......Page 149
7. Conclusions......Page 151
1. Introduction......Page 155
2. The ADME in vivo Profiling Flow Chart......Page 156
3. Considerations about Dosage Regimens......Page 163
4. Conclusions......Page 164
Part III. Physicochemical Strategies......Page 165
1. Introduction......Page 167
2. Chemical Technology Platform......Page 168
3. Chemist-Friendly Library Design Tools......Page 169
4. Standardized Chemistry Development Process......Page 170
5. High-Throughput Analytical Chemistry......Page 171
6. Applications......Page 172
7. Conclusions......Page 175
1. Introduction......Page 177
2. The Solute......Page 178
3. Lipophilicity Systems......Page 179
4. Molecular Descriptors to Investigate the Intermolecular Forces Governing Lipophilicity......Page 183
5. Lipophilicity of Ionized Solutes in Isotropic Systems......Page 185
7. The Contribution of Ionic Interactions in Nonchromatographic Systems......Page 190
9. Conclusions......Page 194
1. Introduction......Page 199
2. Significance of log D and log P......Page 200
3. Computational vs. Experimental Methods......Page 201
4. ElogD7.4: AGeneral Presentation......Page 203
5. Conclusions......Page 211
1. Introduction......Page 215
2. Relationship between Membrane Affinity and Permeation......Page 216
3. Drug Partitioning between Lipid Bilayers andWater......Page 217
4. Drug Permeation across Lipid Bilayers......Page 219
5. Conclusions......Page 230
1. Introduction......Page 233
2. Recent Advances in the PAMPATechnology......Page 242
3. High-Throughput Solubility Measurement by the Self-Calibrating UV Method......Page 246
4. MAD PAMPA for Early Discovery......Page 248
5. Outlook......Page 251
1. Introduction......Page 255
2. Permeability......Page 256
4. Experimental Outline......Page 257
5. Correlations between Physicochemical Properties......Page 264
6. Conclusions......Page 266
1. Introduction......Page 271
2. Methodology......Page 273
3. Solubility Ratios for Compounds with pH-Independent Solubility at Typical Intestinal pH......Page 280
4. Application to BCS Related Calculations......Page 283
5. Application to Forecasting Food Effects on Oral Drug Bioavailability......Page 284
6. The Solubility Ratio for Ionizable Compounds......Page 285
7. Conclusions......Page 291
1. Introduction......Page 293
2. Selecting Stability Profiling Methods......Page 294
3. Methods for Stability Profiling......Page 301
4. Case Studies from the Literature......Page 312
5. Concluding Remarks......Page 315
1. Introduction......Page 319
2. Definitions and Thermodynamic Aspects......Page 321
3. Basic Properties......Page 323
4. Phase Transformations, Kinetic Aspects......Page 333
5. Analytical Technologies......Page 338
6. Conclusions......Page 339
Part IV. Computational Strategies......Page 343
1. Introduction......Page 345
2. Classification of Methodological Approaches......Page 346
3. Fragmental Methods......Page 348
4. Atom Contribution Methods......Page 353
5. Approaches Based on Molecular Lipohilicity Potentials (MLP) and Related Methods......Page 355
6. Approaches Based on Topological Indices......Page 356
7. Approaches Based on Molecular Properties......Page 358
8. Octanol/Water Distribution Coefficients (log......Page 359
9. Conclusions......Page 361
1. Introduction......Page 365
2. The Property Profiles of Acetylcholine......Page 367
3. Correlations between Properties Monitored in vacuo......Page 370
4. Influence of Solvent on Property Space......Page 373
5. Conclusions......Page 376
1. Introduction......Page 379
2. Description of the Method......Page 380
3. An Overview of Major Results......Page 388
4. Conclusions......Page 390
1. Introduction......Page 393
2. Predictive ADME Models Derived by Pharmacophore Modeling......Page 394
3. Conclusions......Page 402
1. Introduction......Page 407
2. BioPrint-Based QSAR Methodology......Page 410
3. Predicting the Inhibition of CYP2D6Using a Synergy Model......Page 420
4. Conclusions......Page 424
1. Introduction......Page 429
2. DEREK for Windows and METEOR......Page 431
3. Human Reasoning......Page 432
4. Using the Logic of Argumentation......Page 433
5. Illustrations of Advice......Page 434
6. Examples......Page 435
7. Conclusions......Page 440
1. Introduction......Page 443
2. Methodological Overview......Page 444
3. Applications of Physiologically Based PK Models......Page 447
4. Conclusions......Page 450
1. Introduction......Page 453
2. Data Processing......Page 455
3. Conclusions......Page 469
Part V. Concluding Chapters......Page 471
Educational and Communication Issues Related to Profiling Compounds for Their Drug-Like Properties......Page 473
1. Introduction......Page 479
2. The Regulatory and Economical Environment......Page 480
3. The R&D Conundrum......Page 482
4. Opportunities to Change the Cost Paradigm......Page 483
5. The Contributions of ADMET Profiling......Page 484
6. Concluding Remarks......Page 489
Subject Index (with page links)......Page 493