The practice of medicinal chemistry:
Saved in:
| Format: | Book |
|---|---|
| Language: | English |
| Published: |
Amsterdam [u.a.]
Elsevier, Acad. Press
2008
|
| Edition: | 3. ed. |
| Subjects: | |
| Online Access: | Inhaltsverzeichnis |
| Physical Description: | XXXVI, 942 S. Ill., graph. Darst. |
| ISBN: | 9780123741943 0123741947 |
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| 245 | 1 | 0 | |a The practice of medicinal chemistry |c ed. by Camille Georges Wermuth |
| 250 | |a 3. ed. | ||
| 264 | 1 | |a Amsterdam [u.a.] |b Elsevier, Acad. Press |c 2008 | |
| 300 | |a XXXVI, 942 S. |b Ill., graph. Darst. | ||
| 336 | |b txt |2 rdacontent | ||
| 337 | |b n |2 rdamedia | ||
| 338 | |b nc |2 rdacarrier | ||
| 650 | 4 | |a Chemistry, Pharmaceutical | |
| 650 | 4 | |a Drugs |x Design | |
| 650 | 4 | |a Models, Chemical | |
| 650 | 4 | |a Pharmaceutical Preparations |x chemistry | |
| 650 | 4 | |a Pharmaceutical chemistry | |
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Record in the Search Index
| _version_ | 1804137928918564864 |
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| adam_text | Biography xxv
Section Editors xxvii
Contributors xxix
Preface to the First Edition xxxv
Preface to the Second Edition xxxvii
Preface to the Third Edition xxxix
Part I General Aspects of Medicinal Chemistry
Section Editor: Hugo Kubinyi 1
1. A History of Drug Discovery 3
Francois Chast
I. Introduction 4
A. The renewal of chemistry 4
B. The dawn of the organic chemistry crosses the birth of biology 5
11. Two Hundred Years of Drug Discoveries 6
A. Pain killers: best-sellers and controversies 6
B. Giving back the heart its youth 10
C. Fight against microbes and viruses 15
D. Drugs for immunosuppression 24
E. Contribution of chemists to the fight against cancer 26
F. Drugs for endocrine disorders 30
G. Anti-acid drugs 34
H. Lipid lowering drugs 35
I. From neurotransmitters to receptors 37
J. Drugs of the mind 41
III. Considerations on Recent Trends in Drug Discovery 49
A. From genetics to DNA technology 49
B. Hopes and limits for drug hunting 52
References 55
2. Medicinal Chemistry: Definitions and Objectives, Drug Activity Phases,
Drug Classification Systems 63
Peter mming
I. Definitions and Objectives 63
A. Medicinal chemistry and related disciplines and terms 63
B. Drugs and drug substances 64
C. Stages of drug development 64
II. Drug Activity Phases 66
A. The pharmaceutical phase 66
B. The pharmacokinetic phase 66
C. The pharmacodynamic phase 67
D. The road to successful drug development? 67
III. Drug Classification Systems 67
A. Classification by target and mechanism of action 68
B. Other classification systems 70
References 71
3. Measurement and Expression of Drug Effects 73
jean-Pierre Nowicki and Bernard Scatton
I. Introduction 73
II. In Vitro Experiments 75
A. Binding studies 75
B. Ligand-receptor interaction-induced functional effects 76
C. Allosteric interaction 78
D. Expression of functional effects for targets other than GPCRS 79
E. Cellular and tissular functional responses 79
III. Ex Vivo Experiments 81
IV. In Vivo Experiments 82
References 83
4. Molecular Drug Targets 85
jean-Pierre Gies and Yves Landry
I. Introduction 86
A. How many drug targets for how many drugs? 86
B. From the drug target to the response of the organism 86
C. Drug binding, affinity and selectivity 87
D. Various ligands for a single target 87
II. Enzymes as Drug Targets 88
A. Targeting human enzymes 88
B. Targeting enzymes selective of invading organisms 89
III. Membrane Transporters as Drug Targets 89
A. Established drug targets among membrane transporters 89
B. Progress in the pharmacological control of membrane transporters 89
IV. Voltage-Gated Ion Channels as Drug Targets 90
A. Voltage-gated sodium channels (Nav channels) 90
B. Voltage-gated calcium channels (Cav channels) 91
C. Potassium channels 91
V. Non-Selective Cation Channels as Drug Targets 92
VI. Direct Ligand-Gated Ion Channels (Receptors with Intrinsic Ion Channel) 93
A. P2X-ATP receptors 94
B. Glutamate-activated receptors 94
C. The Cys-loop receptor superfamily 95
VII. Receptors with Intrinsic Enzyme Activity 95
A. Receptors with guanylate cyclase activity 95
B. Receptors with serine/threonine kinase activity 96
C. Receptors with tyrosine kinase activity • 96
VIII. Receptors Coupled to Various Cytosolic Proteins 97
A. Receptors coupled to the cytosolic tyrosine kinase JAK 97
B. Receptors coupled to the cytosolic Src, Zap70/Syk and Btk tyrosine kinases (immunoreceptors) 97
C. Receptors coupled to the cytosolic serine/threonine kinase IRAK 98
D. Receptors coupled to caspases and to NFkB 98
E. Receptors of the cellular adhesion 99
IX. G-Protein-Coupled Receptors 99
A. How many druggable GPCRs? 100
B. Diversity of G-proteins 101
C. Diversity of GPCR-elicited signaling and related drug targets 101
X. Nuclear Receptors As Drug Targets 103
References 104
5. Drug Targets, Target Identification, Validation and Screening 106
Kenton H. Zavitz, Paul L. Bartel and Adrian N. Hobden
I. Introduction 106
II. Improving the Resolution of Disease Etiology 107
III. Biopharmacuetical Therapies 108
A. Passive immunotherapy 108
IV. Drug Target Identification 109
A. Rare mutations leading to generalized therapies 109
B. Mining the proteome 109
C. Yeast two-hybrid systems 110
D. RNA interference 111
V. Hit-to-Lead 113
A. Cell-based screening 113
B. Intracellular receptors 113
C. Intracellular enzymes 115
D. G-protein-coupled receptors 115
E. Transgenic animals 117
F. Drug metabolism 118
G. Toxicology 118
VI. Clinical Biomarkers 119
VII. Conclusions 119
References 119
Part II Lead Compound Discovery Strategies
Section Editor: John R. Proudfoot 123
6. Strategies in the Search for New Lead Compounds or Original
Working Hypotheses 125
Camille G. VJermuth
I. Introduction 125
A. Hits and leads 125
B. The main hit or lead finding strategies 126
II. First Strategy: Analog Design 126
A. Typical examples 126
B. The different categories of analogs 127
C. Pros and cons of analog design 128
III. Second Strategy: Systematic Screening 129
A. Extensive screening 129
B. Random screening 129
C. High-throughput screening 130
D. Screening of synthesis intermediates 131
E. New leads from old drugs: The SOSA approach 132
IV. Third Strategy: Exploitation of Biological Information 134
A. Exploitation of observations made in humans 134
B. Exploitation of observations made in animals 137
C. Exploitation of observations made in the plant kingdom and in microbiology 137
V. Fourth Strategy: Planned Research and Rational Approaches 138
A. l-DOPA and rarkinsonism 138
IV. Creation and Analysis of FBDD Libraries 234
A. General evaluation and analysis 234
B. Computational approaches 235
C. Use of primary data: sprouting and merging to create secondary libraries 235
V. Nuclear Magnetic Resonance 235
A. ID (ligand-based) screening 235
B. Example 236
C. 2D (protein-based) screening 237
VI. X-ray Crystallography 237
A. General principles and limitations 237
B. Examples 238
VII. Other Biophysical and Biochemical Screening Methods 238
A. Substrate activity screening 238
B. In situ click chemistry 239
C. SPR spectroscopy 239
D. SAR by mass spectroscopy 239
VIII. Methods for Fragment Hit Follow-Up 239
A. How to best reduce false positives (NMR, MS) and false negatives (X-ray) 239
B. Isothermal and differential titration calorimetry and further secondary analysis 240
IX. Trends for the Future 240
References 241
12. Lead-Likeness and Drug-Likeness 244
Alex Polinsky
I. Introduction 244
II. Assessing Drug-Likeness 245
A. Avoiding known threats 245
B. Mimicking known drugs 247
C. Direct property prediction 249
III. Selecting Better Leads: Lead-Likeness 250
A. What is a high-quality lead compound? 250
B. Designing lead-like libraries for biochemical screening 251
IV. Conclusion 253
References 253
13. Web Alert: Using the Internet for Medicinal Chemistry 255
David Cavalla
I. Introduction 255
II. Blogs 256
III. Wikis 257
A. RSS information feeds 257
IV. Compound Information 257
A. Chemspider 257
B. The NIH Roadmap and PubChem 258
C. ChemBank 258
V. Biological Properties of Compounds 258
A. Prediction of biochemical properties 259
B. Molecular datasets 259
C. Information on metabolic properties 260
VI. Drug Information 260
A. DrugBank 260
VII. Physical Chemical Information 261
VIII. Prediction and Calculation of Molecular Properties 261
IX. Chemical Suppliers 263
X. Chemical Synthesis 264
XI. Chemical Software Programs 263
A. Chemical drawing and viewing software 264
B. Various chemoinformatics software 265
C. Datasets for virtual screening 266
XII. Analysis 267
XIII. Chemical Publications 267
A. Journals 267
B. Open access 268
C. Theses 268
XIV. Patent Information 269
A. Japanese patents 270
XV Toxicology 270
XVI. Metasites and Technology Service Provider Databases 272
Part HI Primary Exploration of Structure-Activity Relationships
Section Editor: Camille G. Wermuth 273
14. Molecular Variations in Homologous Series: Vinylogues and Benzologues 275
Camille G. Wermuth
I. Homologous Series 275
A. Definition and classification 275
B. Shapes of the biological response curves 277
C. Results and interpretation 278
II. Vinylogues and Benzologues 283
A. Applications of the vinylogy principle 283
B. Comments 287
References 287
15. Molecular Variations Based on Isosteric Replacements 290
Paola Ciapetti and Bruno Giethlen
I. Introduction 290
II. History: Development of the Isosterism Concept 291
A. The molecular number 291
B. The isosterism concept 292
C. The notion of pseudoatoms and Grimm s hydride displacement law 293
D. Erlenmeyer s expansion of the isosterism concept 293
E. Isoserism criteria: Present conceptions 293
F. The bioisosterism concept: Friedman s and Thornber s definitions 294
III. Currently Encountered Isosteric and Bioisosteric Modifications 294
A. Replacement of univalent atoms or groups 294
B. Interchange of divalent atoms and groups 294
C. Interchange of trivalent atoms and groups 296
D. Ring equivalents 297
E. Groups with similar polar effects: functional equivalents 303
F. Reversal of functional groups 320
IV. Scaffold Hopping 323
A. Successful examples of serendipitous scaffold hopping 323
B. Scaffold hopping and virtual screening 325
V Analysis of the Modifications Resulting from Isosterism 326
A. Structural parameters 327
B. Electronic parameters 327
C. Solubility parameters 327
D. Anomalies in isosterism 328
VI. Minor Metalloids-Toxic Isosters 330
A. Carbon-silicon bioisosterism 330
B. Carbon-boron isosterism 331
C. Bioisosteries involving selenium 333
References 334
16. Ring Transformations 343
Christophe Morice and Camille G. Wermuth
I. Introduction 343
II. Analogical Approaches 343
A. Analogy by ring opening: open-chain analogs 343
B. Analogy by ring closure 345
C. Other analogies 349
III. Disjunctive Approaches 354
A. Cocaine-derived local anesthetics 355
B. Morphinic analgesics 355
C. Dopamine autoreceptor agonists 355
D. CCK antagonists 355
IV. Conjunctive Approaches 356
A. Dopaminergic antagonists 356
B. Glutamate NMDA and AMPA receptor antagonists 358
C. Norfloxacin analogs 359
D. Melatonin analogs 360
V. Conclusion 360
References 360
17. Conformational Restriction and/or Steric Hindrance in Medicinal Chemistry 363
Andre Mann
I. Introduction 363
A. Theoretical points 364
B. On constrainted analogs 366
C. On conformational analysis 367
D. On the natur of Steric effects 368
E. Rigid compounds and bioavailability 368
II. Case studies 368
A. Bradykinin 368
B. Allylic constraints for inducing conformational rigidity 369
C. Diversity-Oriented Synthesis 371
D. Epibatidine bioactive conformation 371
E. Ligands for the Hepatitis C virus 372
F. Nociceptin 374
G. Opioid receptors ligands 374
H. Peptidomimetics for SH2 domains 375
III. Summary and Outlook 377
References 378
18. Homo and Heterodimer Ligands the Twin Drug Approach 380
}ean-Marie Contreras and Wolfgang Sippl
I. Indroduction 380
II. Homodimer and Symmetrical Ligands 383
A. Symmetry in nature 383
B. Homodimers as receptors ligands 383
C. Homodimers as enzyme inhibitors 387
D. Homodimers as DNA ligands 390
E. Homodimers of pharmacological interest 390
III. Heterodimer and Dual Acting Ligands 391
A. Hybrid molecules as ligands of two different receptors 391
B. Hybrids as enzymes inhibitors 394
C. Hybrids acting at one receptor and one enzyme 398
D. Other examples of dual acting drugs 400
IV. Binding Mode Analysis of Identical and Non-identical Twin Drugs 401
A. Identical and non-identical twin drugs interacting with two adjacent binding sites located
on the same macromolecule 403
B. Identical twin drugs interacting with two similar binding sites located on different
monomers of the same macromolecule 405
C. Identical and non-identical twin drugs interacting with two different binding sites located
on different macromolecules 408
V. Conclusion 409
References 410
19. Application Strategies for the Primary Structure-Activity Relationship
Exploration 415
Camitte G. Wermuth
I. Introduction 415
II. Preliminary Considerations 415
III. Hit Optimization Strategies 416
A. Some information about the target is available 417
B. No information about the target is available 418
C. The predominant objective is potency 418
D. The predominant objective is the establishment of SARs 419
E. The predominant objective consists of analog design 422
IV. Application Rules 422
A. Rule number one: the minor modification rule 422
B. Rule number two: the biological logic rule 423
C. Rule number three: the structural logic s rule 424
D. Rule number four: the right substituent choice 424
E. Rule number five: the easy organic synthesis (EOS) rule 425
F. Rule number six: eliminate the chiral centers! 425
G. Rule number seven: the pharmacological logic rule 426
References 426
Part IV Substituents and Functions: Qualitative and Quantitative
Aspects of Structure-Activity Relationships
Section Editor: Han van de Waterbeemd 429
20. Substituent Groups 431
Patrick Bazzini and Camille G. Wermuth
I. Introduction 431
II. Methyl Groups 432
A. Effects on solubility 432
B. Conformational effects 434
C. Electronics effects 435
D. Effects on metabolism 437
E. Extensions to other small alkyl groups 440
III. Effects of Unsaturated Groups 441
A. Vinyl series 442
B. Allylic series 443
C. Acetylenic series 445
D. Cyclenic equivalents of the phenyl ring 447
IV. Effects of Halogenation 448
A. The importance of the halogens in the structure-activity relationship 448
B. Usefulness of the halogens and of cognate functions 451
V. Effects of Hydroxylation 452
A. Effects on solubility 453
B. Effects on the ligand-receptor interaction 453
C. Hydroxylation and metabolism 453
VI. Effects of Thiols and Other Sulfur-Containing Groups 454
A. Drugs containing thiol 454
B. Drugs containing oxidized sulfides 454
C. Drugs containing thiocyanate or thiourea 454
VII. Acidic Functions 456
A. Effects on solubility 456
B. Effects on biological activity 457
VIII. Basic Groups 458
IX. Attachment of Additional Binding Sites 459
A. To increase lipophilicity 459
B. To achieve additional interactions 459
References 460
21. The Role of Functional Groups in Drug-Receptor Interactions 464
Laurent Schaeffer
I. Introduction 464
II. General Principles 464
III. The Importance of the Electrostatic and Steric Match Between Drug and Receptor 465
A. Electrostatic interactions 465
B. Steric interactions 471
C. Enthalpy/entropy compensation 472
IV. The Strengths of Functional Group Contributions to Drug-Receptor Interactions 473
A. Measuring functional group contributions 473
B. The methyl group and other nonpolar substituents 475
C. The hydroxyl group and other hydrogen-bond forming substituents 476
D. Acidic and basic substituents 476
E. Practical applications for the medicinal chemist 476
F. Ligand efficiency 478
V. Cooperative binding 478
References 479
22. Compound Properties and Drug Quality 481
Christopher A. Lipinski
I. Introduction 481
II. Combinatorial Libraries 482
A. Library design for HTS screens 482
B. Experimental synthesis success rate 483
C. Poor solubility and library design 483
D. Importance of the synthesis rate-determining step 483
E. If protocol development is rate determining 484
F. Poor ADME properties - business aspects 484
G. If library production is rate determining 484
H. Relative importance of ADME assays 484
III. Chemistry Control of Intestinal Permeability 484
A. Improving permeability 485
B. Hydrogen bonding and permeability 485
C. Intramolecular hydrogen bonds 485
D. Permeability testing 485
IV. Chemistry Control of Aqueous Solubility 486
A. The definition of poor solubility 486
B. Aqueous solubility and blunt SAR 486
C. Changing the pKa 486
D. Improving aqueous solubility 487
V. In Vitro Potency and Chemistry Control 487
A. Lead complexity 487
VI. Metabolic stability 488
A. ADME computational models 488
B. Limitations of Caco-2 cell culture 488
C. Poor aqueous solubility and permeability assay noise 489
D. Physiologically-relevant screening concentration 489
VII. Acceptable Solubility Guidelines for Permeability Screens 489
A. Batch-mode solubility prediction 490
References 490
23. Quantitative Approaches to Structure-Activity Relationships 491
Han van de Waterbeemd and Sally Rose
I. Introduction to QSAR 491
II. Brief History and Outlook 492
III. QSAR Methodology 493
A. Descriptors 493
B. Methods for building predictive models 496
C. Global and local models, and consensus modeling 503
D. Time-series behavior and autoQSAR 503
E. Experimental design 504
F. Inverse QSAR and multi-objective optimization 505
IV. Practical Applications 505
A. Limitations and appropriate use 505
B. Examples 506
C. Library design, compound acquisition and profiling 508
D. HTS analysis 509
E. Software 509
References 510
Part V Spatial Organization, Receptor Mapping and Molecular Modeling
Section Editor: David J. Triggle 515
24. Overview: The Search for Biologically Useful Chemical Space 517
David J. Triggle
I. Introduction 517
II. How Big is Chemical Space? 518
III. Biological Space is Extremely Small 518
IV. Limited Biological Space as an Effective Biological Strategy 519
References 520
25. Pharmacological Space 521
Andrew L. Hopkins
I. What is Pharmacological Space? 521
II. Chemical Space 521
A. Drug-like space 522
III. Target Space 524
A. Druggability 525
B. Structure-based druggability 526
C. Degrees of druggability 527
D. Druggable genome 529
VI. Conclusions 531
Acknowledgments 531
References 531
26. Optical Isomerism in Drugs 533
Camille G. Wermuth
I. Introduction 533
II. Experimental Facts and Their Interpretation 533
A. Stereoselectivity in biologically active compounds 533
B. The three-point contact model 535
C. Diastereoisomers 537
D. Stereoselectivity ratios 537
E. Pfeiffer s rule 538
III. Optical Isomerism and Pharmacodynamic Aspects 538
A. Differences in potency and antagonism between two enantiomers 538
B. Differences in the pharmacological profile of two enantiomers 539
IV. Optical Isomerism and Pharmacokinetic Effects 539
A. Isomer effects on absorption and distribution 540
B. Isomer effects on metabolism 540
C. Isomer effects on uptake 541
D. Isomer effects on excretion 541
V Practical Considerations 541
A. Racemates or enantiomers? 541
B. The distomer counteracts the eutomer 542
C. Racemic switches 542
D. The distomer is metabolized to unwanted or toxic products 542
E. Deletion of the chiral center 543
F. Usefulness of racemic mixtures 543
References 546
27. Multi-Target Drugs: Strategies and Challenges for Medicinal Chemists 549
Richard Morphy and Z. Rankovic
I. Introduction 549
II. Strategies for Lead Generation 551
III. Main Areas of Focus in DML Discovery (1990-2005) 553
A. SERT-plus DMLs for depression 554
B. Dopamine D2-plus DMLs for schizophrenia 555
C. DMLs targeting the angiotensin system for hypertension 555
D. Histamine Hrplus DMLs for allergies 558
E. AChE-based DMLs for Alzheimer s disease 559
F. PPAR-based DMLs for metabolic disease 560
G. DMLs that inhibit multiple kinases for treating cancer 560
H. DMLs targeting the arachidonic acid cascade 561
I. Mu-opioid-plus DMLs for treating pain 563
IV. Optimization of the Activity Profile and Wider Selectivity 563
V. The Physicochemical Challenge 565
VI. Summary 568
References 569
28. Pharmacophore Identification and Pseudo-Receptor Modeling 572
Wolfgang Sippl
I. Introduction 572
A. Historical background 573
B. Definitions 573
C. Importance of the pharmacophore concept 574
D. Application of pharmacophores 574
II. Methodology 575
A. Pharmacophore modeling 575
III. Advanced approaches 577
A. Structure-based pharmacophores 577
B. Pseudo-receptor models 579
IV. Application study 580
A. Pharmacophore-based screening for novel histamine H3-receptor antagonists 580
B. Pharmacophore determination process 581
C. Pharmacophore-based screening of compound libraries 582
V. Conclusions 584
References 584
29. 3D Quantitative Structure-Property Relationships 587
Thierry hanger and Sharon D. Bryant
I. Introduction 587
II. 3D QSAR Workflow 589
III. 3D QSAR: Conformation Analysis and Molecular Superimposition 590
IV. Calculation of 3D Molecular Field Descriptors 591
V. Statistical Tools 592
VI. Alignment Independent 3D QSAR Techniques 592
VII. Validation Of 3D QSAR Models 594
VIII. Applications 594
A. 3D QSAR study on the structural requirements for inhibiting AChE 594
B. 3D QSAR as a tool to determine molecular similarity 597
IX. Conclusions and Future Directions 601
References 601
30. Protein Crystallography and Drug Discovery 605
jean-hAichel Rondeau and Herman Schreuder
I. Presentation 605
II. Historical Background 607
A. The early days of crystallography 607
B. The current state of the art 607
C. Past and present contributions to drug discovery 608
III. Examples 609
A. Aliskiren (Tekturna™, Rasilez™) 609
B. Nilotinib (Tasigna™) 610
IV. Basic Principles and Methods of Protein Crystallography 611
A. Crystallization 611
B. Data collection 615
C. From diffraction intensities to a molecular structure 615
D. Information content and limitations of crystal structures 618
V. Practical Applications 621
A. Target identification, selection and validation 621
B. Hit/lead generation 623
C. Lead optimization 627
References 629
Part VI Chemical Modifications Influencing the Pharmacokinetic Properties
Section Editor: Richard B. Silverman 635
31. Physiological Aspects Determining the Pharmacokinetic Properties
of Drugs 637
Koen Boussery, Frans M. Belpaire and )ohan Van de Voorde
I. Introduction 637
II. Passage of Drugs Through Biological Barriers 638
A. Transcellular drug transport 638
B. Paracellular drug transport 640
III. Drug Absorption 640
A. Dosage form of the drug 640
B. GI motility and gastric emptying 640
C. GI permeability to the drug 642
D. Perfusion of the GI tract and the first-pass effect 643
IV. Drug Distribution 644
A. Plasma protein binding 644
B. Drug accumulation 645
C. The blood-brain barrier 645
V. Drug Elimination 645
A. Excretion 645
B. Biotransformation 647
VI. Some Pharmacokinetic Parameters and Terminology 648
A. Plasma concentration-time curve 648
B. Volume of distribution 649
C. Clearance 650
D. Elimination half-life (T1/2) 651
E. Bioavailability 651
VII. Variability in Pharmacokinetics 652
A. Genetic factors 652
B. Age 652
C. Drug interactions 653
D. Disease state 653
E. Pregnancy 653
Bibliography 654
32. Biotransformation Reactions and their Enzymes 655
Bernard Testa
I. Introduction 655
II. Functionalization Reactions 656
A. Enzymes catalyzing functionalization reactions 657
B. Reactions of carbon oxidation and reduction 660
C. Oxidation and reduction of N- and S-containing moieties 662
D. Reactions of hydration and hydrolysis 663
III. Conjugation Reactions 664
A. Introduction 664
B. Methylation 665
C. Sulfonation 665
D. Glucuronidation 665
E. Acetylation 667
F. Conjugation with coenzyme A and subsequent reactions 668
G. Conjugation reactions of glutathione 669
IV. Biological Factors Influencing Drug Metabolism 671
V. Concluding Remarks 672
References 672
33. Biotransformations Leading to Toxic Metabolites: Chemical Aspects 674
Anne-Christine Macherey and Patrick M. Dansette
I. Historical Background 674
II. Introduction 675
III. Reactions Involved in the Bioactivation Process 676
A. Oxidation 676
B. Oxidative stress 678
C. Reduction 680
D. Substitutions: hydrolysis and conjugation 682
E. Eliminations 683
F. Further biotransformations leading to the ultimate toxicant 683
IV. Examples of Metabolic Conversions Leading to Toxic Metabolites 685
A. Acetaminophen 685
B. Tienilicacid 687
C. Halothane 688
D. Valproic acid 690
E. Troglitazone 691
V. Conclusion 693
References 694
34. Drug Transport Mechanisms and their Impact on the Disposition
and Effects of Drugs 697
]ean~Michel Scherrmann
I. Introduction 697
II. Biology and Function of Transporters 698
A. Modes of active transport 698
B. Genes and classification 698
C. Basic structure 699
D. Distributions and properties of transporters in tissues 699
III. Transporters in Drug Disposition 702
A. ABC transporters 702
B. SLC transporters 703
IV. Roles of Transporters in Drug Pharmacokinetics, Pharmacodynamics and Toxicology 705
A. Intestinal absorption 705
B. Liver and hepatic clearance 706
C. Blood barriers and tissue distribution 707
D. Kidney and renal clearance 707
V. Conclusion 709
Acknowledgments 709
References 709
35. Strategies for Enhancing Oral Bioavailability and Brain Penetration 711
Brian C. Shook and Paul F. Jackson
I. Introduction 711
II. Enhancing Oral Bioavailability 711
A. Metabolic stability 711
B. Structural rigidity 712
C. pKa 713
D. Hydrogen bond interactions 713
E. Miscellaneous 715
III. Enhancing Brain Penetration 715
A. Metabolic stability 715
B. pKa 716
C. LogP 717
D. Hydrogen bond interactions 718
IV. Conclusion 719
References 719
36. Designing Prodrugs and Bioprecursors 721
Camille G. Wemuth
I. Introduction 721
II. The Different Kinds of Prodrugs 721
A. Definitions and classifications 721
B. The carrier prodrug principle 722
C. The bioprecursor-prodrug principle 723
D. Other categories of prodrugs 724
E. Practical applications of prodrug design 724
III. Carrier Prodrugs: Application Examples 724
A. Improvement of the bioavailability and the biomembrane passage 724
B. Site-specific delivery 728
C. Prolonged duration of action 730
IV. Particular Aspects of Carrier Prodrug Design 731
A. Use of cascade prodrugs 731
B. Codrugs 734
C. Soft drugs 734
D. Carrier prodrugs: conclusion 734
V Bioprecursor Prodrugs: Application Examples 735
A. Oxidative bioactivations 735
B. Reductive bioactivations 737
C. Mixed bioactivation mechanism 738
D. Reactions without change in the state of oxidation 740
VI. Discussion 740
A. Bioprecursors versus carrier prodrugs 740
B. Existence of mixed-type prodrugs 740
VII. Difficulties and Limitations 741
VIII. Conclusion 742
References 742
Part VII Pharmaceutical and Chemical Means to Solubility and
Formulation Problems
Section Editor: Michael}. Bowker 747
37. Preparation of Water-Soluble Compounds through Salt Formation 749
Michael J. Bowker and P. Heinrich Stahl
I. Introduction 749
II. The Solubility of Compounds in Water 750
A. The determination and prediction of solubility 750
B. Ionization of drugs and the importance of pKa 751
III. Acids and Bases Used in Salt Formation 751
IV. Early salt formation studies 753
A. Choice of salt formers 753
B. Prediction of the pH of the salt in solution 754
C. Search for crystalline salts 755
V. Comparison of Different Crystalline Salts 755
A. Melting point 756
B. Aqueous solubility 756
C. Common ion and indifferent electrolyte effects 758
D. Hygroscopicity 758
E. Solubility in co-solvents (water-miscible solvents) 759
F. Dissolution Rate 759
G. Particle size and crystal morphology 760
H. Polymorphism and pseudopolymorphism 760
I. Chemical stability 761
J. Other properties 761
VI. Implications of Salt Selection on Drug Dosage Forms 762
A. Tablet products 762
B. Hard gelatine capsules 763
C. Parenteral solutions 763
D. Oral solutions 763
E. Suspension formulations 763
F. MDI products 764
G. DPI products 764
H. Soft gelatine capsule formulations 764
I. Emulsions, creams and ointments 764
VII. Conclusion 765
References 765
38. Preparation of Water-Soluble Compounds by Covalent Attachment
of Solubilizing Moieties 767
Carnille G. Wermuth
I. Introduction 767
II. Solubilization Strategies 768
A. How will the solubilizing moiety be grafted? 768
B. Where will it be grafted? 768
C. What kind of solubilizing chain will be utilized? 768
III. Acidic Solubilizing Chains 769
A. Direct introduction of acidic functions 769
B. Alkylation of OH and NH functions with acidic chains 769
C. Acylation of OH and NH functions with acidic chains 770
IV. Basic Solubilizing Chains 775
A. Direct attachment of a basic residue 775
B. Bioisosteric exchange of a basic functionality 776
C. Development of a water-soluble prodrug of diazepam 776
D. Attachment of the solubilizing moiety to an alcoholic hydroxyl 777
E. Attachment of the solubilizing moiety to an acidic NH function 779
F. Attachment of the solubilizing moiety to a basic NH2 function 779
G. Attachment of the solubilizing moiety to carboxylic acid functionalities 780
V. Non-ionizable Side Chains 780
A. Glycolyl and glyceryl side chains 780
B. Polyethylene glycol derivatives 781
C. Glucosides and related compounds 781
VI. Concluding Remarks 782
References 783
39. Drug Solubilization with Organic Solvents, or Using Micellar Solutions
or Other Colloidal Dispersed Systems 786
Michael J. Bowkerand P. Heinrich Stahl
I. Introduction 786
II. Factors Controlling Solubility and Absorption 788
A. The nature of drug substances 788
B. The polarity of the solvent system 788
III. Water-cosolvent systems 789
IV. Solubilization Mediated by Surfactants 793
V. Solubilization by Lipid Vehicles 798
A. Emulsions and microemulsions 798
B. Liposomes 802
VI. Nanoparticles and Other Nanocolloidal Technologies 803
VII. Drug Delivery and Clearance Mechanisms of Nanocolloids 806
VIII. Drug Delivery and Accumulation Using Colloidal Systems for the Treatment of Cancer 807
A. Liposome formulations 807
B. Formulations based on nanoparticles, microparticles and conjugated systems 808
IX. Modification of Drug Toxicity by Nanocolloidal Drug Delivery Systems 808
References 809
40. Improvement of Drug Properties by Cyclodextrins 813
Kaneto Uekama and Fumitoshi Himyama
I Introduction 813
II. Pharmaceutically Useful CyDs 813
A. Physicochemical profiles of CyDs 814
B. Biological profiles of CyDs 814
III. Improvement of Drug Properties 816
A. Solubilization 817
B. Stabilization in solution 818
C. Control of solid properties 819
D. Release control 821
E. Enhancement of drug absorption 822
F. Reduction of side-effects 824
G. Use in peptide and protein drugs 826
H. Combined use of CyDs with additives 829
IV. CyD-Based Site-Specific Drug Delivery 831
A. Colon targeting 832
B. Cell targeting 834
C. Brain targeting 835
V Conclusion 835
References 835
41. Chemical and Physicochemical Approaches to Solve Formulation Problems 841
Camille G. VJermuth
I. Introduction 841
II. Increasing Chemical Stability 841
III. Improved Formulation of Peptides and Proteins 844
IV. Dealing with Mesomorphic Crystalline Forms 845
V. Increasing the Melting Point 846
A. Salt or complex formation 846
B. Covalent derivatives 846
C. Introduction of symmetry 847
VI. Gastrointestinal Irritability and Painful Injections 847
A. Gastrointestinal irritability 847
B. Avoidance of painful injections 848
VII. Suppressing Undesirable Organoleptic Properties 849
A. Odor 849
B. Taste 850
References 852
Part VIII Development of New Drugs: Legal and Economic Aspects
Section Editor: Bryan G. Reuben 855
42. Discover a Drug Substance, Formulate and Develop It to a Product 857
Bruno Galli and Bernard Fatter
I. Introduction 857
II. Discover the Drug Substance 857
A. Exploratory research (target finding) 858
B. Early discovery program (lead finding) 858
C. Mature discovery program (lead optimization) 858
D. Research-development interface 859
E. Learning experiences 859
III. Defining Experimental Formulations, The Creative Phase 859
A. Basic thoughts on oral formulation 859
B. What is the purpose of a formulation? 859
C. Suggested sequence of activities prior to start formulation 860
D. Biopharmaceutical classification of compounds 861
E. How do we proceed at a practical level? 861
F. Which formulation principles are used? 862
IV. Pharmaceutical Development in Industry 863
V. Fixing The Quality And Develop The Product in A Regulated Environment 865
References 866
43. Drug Nomenclature 867
R. G. Balocco Mattavelli, J.C. Dong, S. Lasseur and S. Kopp
I. Introduction 867
II. Trade Names and Nonproprietary Names 867
III. Drug Nomenclature 868
A. INNs for pharmaceutical substances 868
B. Common names selected by the International Standards Organization (ISO) 874
IV. Use and Protection of Nonproprietary Names 874
A. Use of nonproprietary names 874
B. Protection of nonproprietary names 874
V. Summary 875
References 875
Annex 875
44. Legal Aspects of Product Protection: What a Medicinal Chemist Should
Know about Patent Protection 878
Maria Souleau
I. Introduction 878
A. History of the patent-system prior to 1883 878
B. Main conventions and treaties 879
II. Definition of A Patent - Patent Rights 882
III. Kind of Inventions 882
IV. Subjects of Patents: Basic and Formal Requirements for Filing a Patent 882
A. Basic requirements 882
B. Formal requirements 888
V. Lifetime of Patents 890
VI. Ownership of Patents 890
VII. Infringement of a Patent 890
VIII. Patents as a Source of Information 891
IX. Patenting in the Pharmaceutical Industries 891
X. Conclusion 892
References 892
45. The Consumption and Production of Pharmaceuticals 894
Bryan G. Reuben
I. Important Drugs 895
A. The top-earning drugs 895
B. The most widely prescribed drugs 895
C. National differences in prescribing 899
II. Sources of Drugs 902
A. Vegetable sources 902
B. Animal sources 902
C. Biological sources 902
D. Fermentation 903
E. Chemical synthesis 903
III. Manufacture of Drugs 903
A. Good manufacturing practice 904
B. Plant design 904
C. Formulation and packaging-sterile products 905
D. Choice of reagents 906
E. Green chemistry 906
F. Downstream processing 907
G. Outsourcing 907
IV. Social and Economic Factors 909
A. Pattern and cost of innovation 909
B. Patents 910
C. Orphan drugs 911
D. Generic Pharmaceuticals 912
E. Parallel trade 914
F. Cost containment measures 914
G. Pharmacoeconomics 916
V. The Future of the Pharmaceutical Industry 918
A. Trends in Pharmaceuticals 919
B. Conclusion 920
References 920
Index 923
|
| adam_txt |
Biography xxv
Section Editors xxvii
Contributors xxix
Preface to the First Edition xxxv
Preface to the Second Edition xxxvii
Preface to the Third Edition xxxix
Part I General Aspects of Medicinal Chemistry
Section Editor: Hugo Kubinyi 1
1. A History of Drug Discovery 3
Francois Chast
I. Introduction 4
A. The renewal of chemistry 4
B. The dawn of the organic chemistry crosses the birth of biology 5
11. Two Hundred Years of Drug Discoveries 6
A. Pain killers: best-sellers and controversies 6
B. Giving back the heart its youth 10
C. Fight against microbes and viruses 15
D. Drugs for immunosuppression 24
E. Contribution of chemists to the fight against cancer 26
F. Drugs for endocrine disorders 30
G. Anti-acid drugs 34
H. Lipid lowering drugs 35
I. From neurotransmitters to receptors 37
J. Drugs of the mind 41
III. Considerations on Recent Trends in Drug Discovery 49
A. From genetics to DNA technology 49
B. Hopes and limits for drug hunting 52
References 55
2. Medicinal Chemistry: Definitions and Objectives, Drug Activity Phases,
Drug Classification Systems 63
Peter \mming
I. Definitions and Objectives 63
A. Medicinal chemistry and related disciplines and terms 63
B. Drugs and drug substances 64
C. Stages of drug development 64
II. Drug Activity Phases 66
A. The pharmaceutical phase 66
B. The pharmacokinetic phase 66
C. The pharmacodynamic phase 67
D. The road to successful drug development? 67
III. Drug Classification Systems 67
A. Classification by target and mechanism of action 68
B. Other classification systems 70
References 71
3. Measurement and Expression of Drug Effects 73
jean-Pierre Nowicki and Bernard Scatton
I. Introduction 73
II. In Vitro Experiments 75
A. Binding studies 75
B. Ligand-receptor interaction-induced functional effects 76
C. Allosteric interaction 78
D. Expression of functional effects for targets other than GPCRS 79
E. Cellular and tissular functional responses 79
III. Ex Vivo Experiments 81
IV. In Vivo Experiments 82
References 83
4. Molecular Drug Targets 85
jean-Pierre Gies and Yves Landry
I. Introduction 86
A. How many drug targets for how many drugs? 86
B. From the drug target to the response of the organism 86
C. Drug binding, affinity and selectivity 87
D. Various ligands for a single target 87
II. Enzymes as Drug Targets 88
A. Targeting human enzymes 88
B. Targeting enzymes selective of invading organisms 89
III. Membrane Transporters as Drug Targets 89
A. Established drug targets among membrane transporters 89
B. Progress in the pharmacological control of membrane transporters 89
IV. Voltage-Gated Ion Channels as Drug Targets 90
A. Voltage-gated sodium channels (Nav channels) 90
B. Voltage-gated calcium channels (Cav channels) 91
C. Potassium channels 91
V. Non-Selective Cation Channels as Drug Targets 92
VI. Direct Ligand-Gated Ion Channels (Receptors with Intrinsic Ion Channel) 93
A. P2X-ATP receptors 94
B. Glutamate-activated receptors 94
C. The "Cys-loop receptor superfamily" 95
VII. Receptors with Intrinsic Enzyme Activity 95
A. Receptors with guanylate cyclase activity 95
B. Receptors with serine/threonine kinase activity 96
C. Receptors with tyrosine kinase activity • 96
VIII. Receptors Coupled to Various Cytosolic Proteins 97
A. Receptors coupled to the cytosolic tyrosine kinase JAK 97
B. Receptors coupled to the cytosolic Src, Zap70/Syk and Btk tyrosine kinases (immunoreceptors) 97
C. Receptors coupled to the cytosolic serine/threonine kinase IRAK 98
D. Receptors coupled to caspases and to NFkB 98
E. Receptors of the cellular adhesion 99
IX. G-Protein-Coupled Receptors 99
A. How many druggable GPCRs? 100
B. Diversity of G-proteins 101
C. Diversity of GPCR-elicited signaling and related drug targets 101
X. Nuclear Receptors As Drug Targets 103
References 104
5. Drug Targets, Target Identification, Validation and Screening 106
Kenton H. Zavitz, Paul L. Bartel and Adrian N. Hobden
I. Introduction 106
II. Improving the Resolution of Disease Etiology 107
III. Biopharmacuetical Therapies 108
A. Passive immunotherapy 108
IV. Drug Target Identification 109
A. Rare mutations leading to generalized therapies 109
B. Mining the proteome 109
C. Yeast two-hybrid systems 110
D. RNA interference 111
V. Hit-to-Lead 113
A. Cell-based screening 113
B. Intracellular receptors 113
C. Intracellular enzymes 115
D. G-protein-coupled receptors 115
E. Transgenic animals 117
F. Drug metabolism 118
G. Toxicology 118
VI. Clinical Biomarkers 119
VII. Conclusions 119
References 119
Part II Lead Compound Discovery Strategies
Section Editor: John R. Proudfoot 123
6. Strategies in the Search for New Lead Compounds or Original
Working Hypotheses 125
Camille G. VJermuth
I. Introduction 125
A. Hits and leads 125
B. The main hit or lead finding strategies 126
II. First Strategy: Analog Design 126
A. Typical examples 126
B. The different categories of analogs 127
C. Pros and cons of analog design 128
III. Second Strategy: Systematic Screening 129
A. Extensive screening 129
B. Random screening 129
C. High-throughput screening 130
D. Screening of synthesis intermediates 131
E. New leads from old drugs: The SOSA approach 132
IV. Third Strategy: Exploitation of Biological Information 134
A. Exploitation of observations made in humans 134
B. Exploitation of observations made in animals 137
C. Exploitation of observations made in the plant kingdom and in microbiology 137
V. Fourth Strategy: Planned Research and Rational Approaches 138
A. l-DOPA and rarkinsonism 138
IV. Creation and Analysis of FBDD Libraries 234
A. General evaluation and analysis 234
B. Computational approaches 235
C. Use of primary data: sprouting and merging to create secondary libraries 235
V. Nuclear Magnetic Resonance 235
A. ID (ligand-based) screening 235
B. Example 236
C. 2D (protein-based) screening 237
VI. X-ray Crystallography 237
A. General principles and limitations 237
B. Examples 238
VII. Other Biophysical and Biochemical Screening Methods 238
A. Substrate activity screening 238
B. In situ click chemistry 239
C. SPR spectroscopy 239
D. SAR by mass spectroscopy 239
VIII. Methods for Fragment Hit Follow-Up 239
A. How to best reduce false positives (NMR, MS) and false negatives (X-ray) 239
B. Isothermal and differential titration calorimetry and further secondary analysis 240
IX. Trends for the Future 240
References 241
12. Lead-Likeness and Drug-Likeness 244
Alex Polinsky
I. Introduction 244
II. Assessing "Drug-Likeness" 245
A. Avoiding known threats 245
B. Mimicking known drugs 247
C. Direct property prediction 249
III. Selecting Better Leads: "Lead-Likeness" 250
A. What is a "high-quality" lead compound? 250
B. Designing "lead-like" libraries for biochemical screening 251
IV. Conclusion 253
References 253
13. Web Alert: Using the Internet for Medicinal Chemistry 255
David Cavalla
I. Introduction 255
II. Blogs 256
III. Wikis 257
A. RSS information feeds 257
IV. Compound Information 257
A. Chemspider 257
B. The NIH Roadmap and PubChem 258
C. ChemBank 258
V. Biological Properties of Compounds 258
A. Prediction of biochemical properties 259
B. Molecular datasets 259
C. Information on metabolic properties 260
VI. Drug Information 260
A. DrugBank 260
VII. Physical Chemical Information 261
VIII. Prediction and Calculation of Molecular Properties 261
IX. Chemical Suppliers 263
X. Chemical Synthesis 264
XI. Chemical Software Programs 263
A. Chemical drawing and viewing software 264
B. Various chemoinformatics software 265
C. Datasets for virtual screening 266
XII. Analysis 267
XIII. Chemical Publications 267
A. Journals 267
B. Open access 268
C. Theses 268
XIV. Patent Information 269
A. Japanese patents 270
XV Toxicology 270
XVI. Metasites and Technology Service Provider Databases 272
Part HI Primary Exploration of Structure-Activity Relationships
Section Editor: Camille G. Wermuth 273
14. Molecular Variations in Homologous Series: Vinylogues and Benzologues 275
Camille G. Wermuth
I. Homologous Series 275
A. Definition and classification 275
B. Shapes of the biological response curves 277
C. Results and interpretation 278
II. Vinylogues and Benzologues 283
A. Applications of the vinylogy principle 283
B. Comments 287
References 287
15. Molecular Variations Based on Isosteric Replacements 290
Paola Ciapetti and Bruno Giethlen
I. Introduction 290
II. History: Development of the Isosterism Concept 291
A. The molecular number 291
B. The isosterism concept 292
C. The notion of pseudoatoms and Grimm's hydride displacement law 293
D. Erlenmeyer's expansion of the isosterism concept 293
E. Isoserism criteria: Present conceptions 293
F. The bioisosterism concept: Friedman's and Thornber's definitions 294
III. Currently Encountered Isosteric and Bioisosteric Modifications 294
A. Replacement of univalent atoms or groups 294
B. Interchange of divalent atoms and groups 294
C. Interchange of trivalent atoms and groups 296
D. Ring equivalents 297
E. Groups with similar polar effects: functional equivalents 303
F. Reversal of functional groups 320
IV. Scaffold Hopping 323
A. Successful examples of serendipitous scaffold hopping 323
B. Scaffold hopping and virtual screening 325
V Analysis of the Modifications Resulting from Isosterism 326
A. Structural parameters 327
B. Electronic parameters 327
C. Solubility parameters 327
D. Anomalies in isosterism 328
VI. Minor Metalloids-Toxic Isosters 330
A. Carbon-silicon bioisosterism 330
B. Carbon-boron isosterism 331
C. Bioisosteries involving selenium 333
References 334
16. Ring Transformations 343
Christophe Morice and Camille G. Wermuth
I. Introduction 343
II. Analogical Approaches 343
A. Analogy by ring opening: open-chain analogs 343
B. Analogy by ring closure 345
C. Other analogies 349
III. Disjunctive Approaches 354
A. Cocaine-derived local anesthetics 355
B. Morphinic analgesics 355
C. Dopamine autoreceptor agonists 355
D. CCK antagonists 355
IV. Conjunctive Approaches 356
A. Dopaminergic antagonists 356
B. Glutamate NMDA and AMPA receptor antagonists 358
C. Norfloxacin analogs 359
D. Melatonin analogs 360
V. Conclusion 360
References 360
17. Conformational Restriction and/or Steric Hindrance in Medicinal Chemistry 363
Andre Mann
I. Introduction 363
A. Theoretical points 364
B. On constrainted analogs 366
C. On conformational analysis 367
D. On the natur of Steric effects 368
E. Rigid compounds and bioavailability 368
II. Case studies 368
A. Bradykinin 368
B. Allylic constraints for inducing conformational rigidity 369
C. Diversity-Oriented Synthesis 371
D. Epibatidine bioactive conformation 371
E. Ligands for the Hepatitis C virus 372
F. Nociceptin 374
G. Opioid receptors ligands 374
H. Peptidomimetics for SH2 domains 375
III. Summary and Outlook 377
References 378
18. Homo and Heterodimer Ligands the Twin Drug Approach 380
}ean-Marie Contreras and Wolfgang Sippl
I. Indroduction 380
II. Homodimer and Symmetrical Ligands 383
A. Symmetry in nature 383
B. Homodimers as receptors ligands 383
C. Homodimers as enzyme inhibitors 387
D. Homodimers as DNA ligands 390
E. Homodimers of pharmacological interest 390
III. Heterodimer and Dual Acting Ligands 391
A. Hybrid molecules as ligands of two different receptors 391
B. Hybrids as enzymes inhibitors 394
C. Hybrids acting at one receptor and one enzyme 398
D. Other examples of dual acting drugs 400
IV. Binding Mode Analysis of Identical and Non-identical Twin Drugs 401
A. Identical and non-identical twin drugs interacting with two adjacent binding sites located
on the same macromolecule 403
B. Identical twin drugs interacting with two similar binding sites located on different
monomers of the same macromolecule 405
C. Identical and non-identical twin drugs interacting with two different binding sites located
on different macromolecules 408
V. Conclusion 409
References 410
19. Application Strategies for the Primary Structure-Activity Relationship
Exploration 415
Camitte G. Wermuth
I. Introduction 415
II. Preliminary Considerations 415
III. Hit Optimization Strategies 416
A. Some information about the target is available 417
B. No information about the target is available 418
C. The predominant objective is potency 418
D. The predominant objective is the establishment of SARs 419
E. The predominant objective consists of analog design 422
IV. Application Rules 422
A. Rule number one: the minor modification rule 422
B. Rule number two: the biological logic rule 423
C. Rule number three: the structural logic's rule 424
D. Rule number four: the right substituent choice 424
E. Rule number five: the easy organic synthesis (EOS) rule 425
F. Rule number six: eliminate the chiral centers! 425
G. Rule number seven: the pharmacological logic rule 426
References 426
Part IV Substituents and Functions: Qualitative and Quantitative
Aspects of Structure-Activity Relationships
Section Editor: Han van de Waterbeemd 429
20. Substituent Groups 431
Patrick Bazzini and Camille G. Wermuth
I. Introduction 431
II. Methyl Groups 432
A. Effects on solubility 432
B. Conformational effects 434
C. Electronics effects 435
D. Effects on metabolism 437
E. Extensions to other small alkyl groups 440
III. Effects of Unsaturated Groups 441
A. Vinyl series 442
B. Allylic series 443
C. Acetylenic series 445
D. Cyclenic equivalents of the phenyl ring 447
IV. Effects of Halogenation 448
A. The importance of the halogens in the structure-activity relationship 448
B. Usefulness of the halogens and of cognate functions 451
V. Effects of Hydroxylation 452
A. Effects on solubility 453
B. Effects on the ligand-receptor interaction 453
C. Hydroxylation and metabolism 453
VI. Effects of Thiols and Other Sulfur-Containing Groups 454
A. Drugs containing thiol 454
B. Drugs containing oxidized sulfides 454
C. Drugs containing thiocyanate or thiourea 454
VII. Acidic Functions 456
A. Effects on solubility 456
B. Effects on biological activity 457
VIII. Basic Groups 458
IX. Attachment of Additional Binding Sites 459
A. To increase lipophilicity 459
B. To achieve additional interactions 459
References 460
21. The Role of Functional Groups in Drug-Receptor Interactions 464
Laurent Schaeffer
I. Introduction 464
II. General Principles 464
III. The Importance of the Electrostatic and Steric Match Between Drug and Receptor 465
A. Electrostatic interactions 465
B. Steric interactions 471
C. Enthalpy/entropy compensation 472
IV. The Strengths of Functional Group Contributions to Drug-Receptor Interactions 473
A. Measuring functional group contributions 473
B. The methyl group and other nonpolar substituents 475
C. The hydroxyl group and other hydrogen-bond forming substituents 476
D. Acidic and basic substituents 476
E. Practical applications for the medicinal chemist 476
F. Ligand efficiency 478
V. Cooperative binding 478
References 479
22. Compound Properties and Drug Quality 481
Christopher A. Lipinski
I. Introduction 481
II. Combinatorial Libraries 482
A. Library design for HTS screens 482
B. Experimental synthesis success rate 483
C. Poor solubility and library design 483
D. Importance of the synthesis rate-determining step 483
E. If protocol development is rate determining 484
F. Poor ADME properties - business aspects 484
G. If library production is rate determining 484
H. Relative importance of ADME assays 484
III. Chemistry Control of Intestinal Permeability 484
A. Improving permeability 485
B. Hydrogen bonding and permeability 485
C. Intramolecular hydrogen bonds 485
D. Permeability testing 485
IV. Chemistry Control of Aqueous Solubility 486
A. The definition of poor solubility 486
B. Aqueous solubility and blunt SAR 486
C. Changing the pKa 486
D. Improving aqueous solubility 487
V. In Vitro Potency and Chemistry Control 487
A. Lead complexity 487
VI. Metabolic stability 488
A. ADME computational models 488
B. Limitations of Caco-2 cell culture 488
C. Poor aqueous solubility and permeability assay noise 489
D. Physiologically-relevant screening concentration 489
VII. Acceptable Solubility Guidelines for Permeability Screens 489
A. Batch-mode solubility prediction 490
References 490
23. Quantitative Approaches to Structure-Activity Relationships 491
Han van de Waterbeemd and Sally Rose
I. Introduction to QSAR 491
II. Brief History and Outlook 492
III. QSAR Methodology 493
A. Descriptors 493
B. Methods for building predictive models 496
C. Global and local models, and consensus modeling 503
D. Time-series behavior and autoQSAR 503
E. Experimental design 504
F. Inverse QSAR and multi-objective optimization 505
IV. Practical Applications 505
A. Limitations and appropriate use 505
B. Examples 506
C. Library design, compound acquisition and profiling 508
D. HTS analysis 509
E. Software 509
References 510
Part V Spatial Organization, Receptor Mapping and Molecular Modeling
Section Editor: David J. Triggle 515
24. Overview: The Search for Biologically Useful Chemical Space 517
David J. Triggle
I. Introduction 517
II. How Big is Chemical Space? 518
III. Biological Space is Extremely Small 518
IV. Limited Biological Space as an Effective Biological Strategy 519
References 520
25. Pharmacological Space 521
Andrew L. Hopkins
I. What is Pharmacological Space? 521
II. Chemical Space 521
A. Drug-like space 522
III. Target Space 524
A. Druggability 525
B. Structure-based druggability 526
C. Degrees of druggability 527
D. Druggable genome 529
VI. Conclusions 531
Acknowledgments 531
References 531
26. Optical Isomerism in Drugs 533
Camille G. Wermuth
I. Introduction 533
II. Experimental Facts and Their Interpretation 533
A. Stereoselectivity in biologically active compounds 533
B. The three-point contact model 535
C. Diastereoisomers 537
D. Stereoselectivity ratios 537
E. Pfeiffer's rule 538
III. Optical Isomerism and Pharmacodynamic Aspects 538
A. Differences in potency and antagonism between two enantiomers 538
B. Differences in the pharmacological profile of two enantiomers 539
IV. Optical Isomerism and Pharmacokinetic Effects 539
A. Isomer effects on absorption and distribution 540
B. Isomer effects on metabolism 540
C. Isomer effects on uptake 541
D. Isomer effects on excretion 541
V Practical Considerations 541
A. Racemates or enantiomers? 541
B. The distomer counteracts the eutomer 542
C. Racemic switches 542
D. The distomer is metabolized to unwanted or toxic products 542
E. Deletion of the chiral center 543
F. Usefulness of racemic mixtures 543
References 546
27. Multi-Target Drugs: Strategies and Challenges for Medicinal Chemists 549
Richard Morphy and Z. Rankovic
I. Introduction 549
II. Strategies for Lead Generation 551
III. Main Areas of Focus in DML Discovery (1990-2005) 553
A. SERT-plus DMLs for depression 554
B. Dopamine D2-plus DMLs for schizophrenia 555
C. DMLs targeting the angiotensin system for hypertension 555
D. Histamine Hrplus DMLs for allergies 558
E. AChE-based DMLs for Alzheimer's disease 559
F. PPAR-based DMLs for metabolic disease 560
G. DMLs that inhibit multiple kinases for treating cancer 560
H. DMLs targeting the arachidonic acid cascade 561
I. Mu-opioid-plus DMLs for treating pain 563
IV. Optimization of the Activity Profile and Wider Selectivity 563
V. The Physicochemical Challenge 565
VI. Summary 568
References 569
28. Pharmacophore Identification and Pseudo-Receptor Modeling 572
Wolfgang Sippl
I. Introduction 572
A. Historical background 573
B. Definitions 573
C. Importance of the pharmacophore concept 574
D. Application of pharmacophores 574
II. Methodology 575
A. Pharmacophore modeling 575
III. Advanced approaches 577
A. Structure-based pharmacophores 577
B. Pseudo-receptor models 579
IV. Application study 580
A. Pharmacophore-based screening for novel histamine H3-receptor antagonists 580
B. Pharmacophore determination process 581
C. Pharmacophore-based screening of compound libraries 582
V. Conclusions 584
References 584
29. 3D Quantitative Structure-Property Relationships 587
Thierry hanger and Sharon D. Bryant
I. Introduction 587
II. 3D QSAR Workflow 589
III. 3D QSAR: Conformation Analysis and Molecular Superimposition 590
IV. Calculation of 3D Molecular Field Descriptors 591
V. Statistical Tools 592
VI. Alignment Independent 3D QSAR Techniques 592
VII. Validation Of 3D QSAR Models 594
VIII. Applications 594
A. 3D QSAR study on the structural requirements for inhibiting AChE 594
B. 3D QSAR as a tool to determine molecular similarity 597
IX. Conclusions and Future Directions 601
References 601
30. Protein Crystallography and Drug Discovery 605
jean-hAichel Rondeau and Herman Schreuder
I. Presentation 605
II. Historical Background 607
A. The early days of crystallography 607
B. The current state of the art 607
C. Past and present contributions to drug discovery 608
III. Examples 609
A. Aliskiren (Tekturna™, Rasilez™) 609
B. Nilotinib (Tasigna™) 610
IV. Basic Principles and Methods of Protein Crystallography 611
A. Crystallization 611
B. Data collection 615
C. From diffraction intensities to a molecular structure 615
D. Information content and limitations of crystal structures 618
V. Practical Applications 621
A. Target identification, selection and validation 621
B. Hit/lead generation 623
C. Lead optimization 627
References 629
Part VI Chemical Modifications Influencing the Pharmacokinetic Properties
Section Editor: Richard B. Silverman 635
31. Physiological Aspects Determining the Pharmacokinetic Properties
of Drugs 637
Koen Boussery, Frans M. Belpaire and )ohan Van de Voorde
I. Introduction 637
II. Passage of Drugs Through Biological Barriers 638
A. Transcellular drug transport 638
B. Paracellular drug transport 640
III. Drug Absorption 640
A. Dosage form of the drug 640
B. GI motility and gastric emptying 640
C. GI permeability to the drug 642
D. Perfusion of the GI tract and the first-pass effect 643
IV. Drug Distribution 644
A. Plasma protein binding 644
B. Drug accumulation 645
C. The blood-brain barrier 645
V. Drug Elimination 645
A. Excretion 645
B. Biotransformation 647
VI. Some Pharmacokinetic Parameters and Terminology 648
A. Plasma concentration-time curve 648
B. Volume of distribution 649
C. Clearance 650
D. Elimination half-life (T1/2) 651
E. Bioavailability 651
VII. Variability in Pharmacokinetics 652
A. Genetic factors 652
B. Age 652
C. Drug interactions 653
D. Disease state 653
E. Pregnancy 653
Bibliography 654
32. Biotransformation Reactions and their Enzymes 655
Bernard Testa
I. Introduction 655
II. Functionalization Reactions 656
A. Enzymes catalyzing functionalization reactions 657
B. Reactions of carbon oxidation and reduction 660
C. Oxidation and reduction of N- and S-containing moieties 662
D. Reactions of hydration and hydrolysis 663
III. Conjugation Reactions 664
A. Introduction 664
B. Methylation 665
C. Sulfonation 665
D. Glucuronidation 665
E. Acetylation 667
F. Conjugation with coenzyme A and subsequent reactions 668
G. Conjugation reactions of glutathione 669
IV. Biological Factors Influencing Drug Metabolism 671
V. Concluding Remarks 672
References 672
33. Biotransformations Leading to Toxic Metabolites: Chemical Aspects 674
Anne-Christine Macherey and Patrick M. Dansette
I. Historical Background 674
II. Introduction 675
III. Reactions Involved in the Bioactivation Process 676
A. Oxidation 676
B. Oxidative stress 678
C. Reduction 680
D. Substitutions: hydrolysis and conjugation 682
E. Eliminations 683
F. Further biotransformations leading to the ultimate toxicant 683
IV. Examples of Metabolic Conversions Leading to Toxic Metabolites 685
A. Acetaminophen 685
B. Tienilicacid 687
C. Halothane 688
D. Valproic acid 690
E. Troglitazone 691
V. Conclusion 693
References 694
34. Drug Transport Mechanisms and their Impact on the Disposition
and Effects of Drugs 697
]ean~Michel Scherrmann
I. Introduction 697
II. Biology and Function of Transporters 698
A. Modes of active transport 698
B. Genes and classification 698
C. Basic structure 699
D. Distributions and properties of transporters in tissues 699
III. Transporters in Drug Disposition 702
A. ABC transporters 702
B. SLC transporters 703
IV. Roles of Transporters in Drug Pharmacokinetics, Pharmacodynamics and Toxicology 705
A. Intestinal absorption 705
B. Liver and hepatic clearance 706
C. Blood barriers and tissue distribution 707
D. Kidney and renal clearance 707
V. Conclusion 709
Acknowledgments 709
References 709
35. Strategies for Enhancing Oral Bioavailability and Brain Penetration 711
Brian C. Shook and Paul F. Jackson
I. Introduction 711
II. Enhancing Oral Bioavailability 711
A. Metabolic stability 711
B. Structural rigidity 712
C. pKa 713
D. Hydrogen bond interactions 713
E. Miscellaneous 715
III. Enhancing Brain Penetration 715
A. Metabolic stability 715
B. pKa 716
C. LogP 717
D. Hydrogen bond interactions 718
IV. Conclusion 719
References 719
36. Designing Prodrugs and Bioprecursors 721
Camille G. Wemuth
I. Introduction 721
II. The Different Kinds of Prodrugs 721
A. Definitions and classifications 721
B. The carrier prodrug principle 722
C. The bioprecursor-prodrug principle 723
D. Other categories of prodrugs 724
E. Practical applications of prodrug design 724
III. Carrier Prodrugs: Application Examples 724
A. Improvement of the bioavailability and the biomembrane passage 724
B. Site-specific delivery 728
C. Prolonged duration of action 730
IV. Particular Aspects of Carrier Prodrug Design 731
A. Use of cascade prodrugs 731
B. Codrugs 734
C. Soft drugs 734
D. Carrier prodrugs: conclusion 734
V Bioprecursor Prodrugs: Application Examples 735
A. Oxidative bioactivations 735
B. Reductive bioactivations 737
C. Mixed bioactivation mechanism 738
D. Reactions without change in the state of oxidation 740
VI. Discussion 740
A. Bioprecursors versus carrier prodrugs 740
B. Existence of mixed-type prodrugs 740
VII. Difficulties and Limitations 741
VIII. Conclusion 742
References 742
Part VII Pharmaceutical and Chemical Means to Solubility and
Formulation Problems
Section Editor: Michael}. Bowker 747
37. Preparation of Water-Soluble Compounds through Salt Formation 749
Michael J. Bowker and P. Heinrich Stahl
I. Introduction 749
II. The Solubility of Compounds in Water 750
A. The determination and prediction of solubility 750
B. Ionization of drugs and the importance of pKa 751
III. Acids and Bases Used in Salt Formation 751
IV. Early salt formation studies 753
A. Choice of salt formers 753
B. Prediction of the pH of the salt in solution 754
C. Search for crystalline salts 755
V. Comparison of Different Crystalline Salts 755
A. Melting point 756
B. Aqueous solubility 756
C. Common ion and indifferent electrolyte effects 758
D. Hygroscopicity 758
E. Solubility in co-solvents (water-miscible solvents) 759
F. Dissolution Rate 759
G. Particle size and crystal morphology 760
H. Polymorphism and pseudopolymorphism 760
I. Chemical stability 761
J. Other properties 761
VI. Implications of Salt Selection on Drug Dosage Forms 762
A. Tablet products 762
B. Hard gelatine capsules 763
C. Parenteral solutions 763
D. Oral solutions 763
E. Suspension formulations 763
F. MDI products 764
G. DPI products 764
H. Soft gelatine capsule formulations 764
I. Emulsions, creams and ointments 764
VII. Conclusion 765
References 765
38. Preparation of Water-Soluble Compounds by Covalent Attachment
of Solubilizing Moieties 767
Carnille G. Wermuth
I. Introduction 767
II. Solubilization Strategies 768
A. How will the solubilizing moiety be grafted? 768
B. Where will it be grafted? 768
C. What kind of solubilizing chain will be utilized? 768
III. Acidic Solubilizing Chains 769
A. Direct introduction of acidic functions 769
B. Alkylation of OH and NH functions with acidic chains 769
C. Acylation of OH and NH functions with acidic chains 770
IV. Basic Solubilizing Chains 775
A. Direct attachment of a basic residue 775
B. Bioisosteric exchange of a basic functionality 776
C. Development of a water-soluble prodrug of diazepam 776
D. Attachment of the solubilizing moiety to an alcoholic hydroxyl 777
E. Attachment of the solubilizing moiety to an acidic NH function 779
F. Attachment of the solubilizing moiety to a basic NH2 function 779
G. Attachment of the solubilizing moiety to carboxylic acid functionalities 780
V. Non-ionizable Side Chains 780
A. Glycolyl and glyceryl side chains 780
B. Polyethylene glycol derivatives 781
C. Glucosides and related compounds 781
VI. Concluding Remarks 782
References 783
39. Drug Solubilization with Organic Solvents, or Using Micellar Solutions
or Other Colloidal Dispersed Systems 786
Michael J. Bowkerand P. Heinrich Stahl
I. Introduction 786
II. Factors Controlling Solubility and Absorption 788
A. The nature of drug substances 788
B. The polarity of the solvent system 788
III. Water-cosolvent systems 789
IV. Solubilization Mediated by Surfactants 793
V. Solubilization by Lipid Vehicles 798
A. Emulsions and microemulsions 798
B. Liposomes 802
VI. Nanoparticles and Other Nanocolloidal Technologies 803
VII. Drug Delivery and Clearance Mechanisms of Nanocolloids 806
VIII. Drug Delivery and Accumulation Using Colloidal Systems for the Treatment of Cancer 807
A. Liposome formulations 807
B. Formulations based on nanoparticles, microparticles and conjugated systems 808
IX. Modification of Drug Toxicity by Nanocolloidal Drug Delivery Systems 808
References 809
40. Improvement of Drug Properties by Cyclodextrins 813
Kaneto Uekama and Fumitoshi Himyama
I Introduction 813
II. Pharmaceutically Useful CyDs 813
A. Physicochemical profiles of CyDs 814
B. Biological profiles of CyDs 814
III. Improvement of Drug Properties 816
A. Solubilization 817
B. Stabilization in solution 818
C. Control of solid properties 819
D. Release control 821
E. Enhancement of drug absorption 822
F. Reduction of side-effects 824
G. Use in peptide and protein drugs 826
H. Combined use of CyDs with additives 829
IV. CyD-Based Site-Specific Drug Delivery 831
A. Colon targeting 832
B. Cell targeting 834
C. Brain targeting 835
V Conclusion 835
References 835
41. Chemical and Physicochemical Approaches to Solve Formulation Problems 841
Camille G. VJermuth
I. Introduction 841
II. Increasing Chemical Stability 841
III. Improved Formulation of Peptides and Proteins 844
IV. Dealing with Mesomorphic Crystalline Forms 845
V. Increasing the Melting Point 846
A. Salt or complex formation 846
B. Covalent derivatives 846
C. Introduction of symmetry 847
VI. Gastrointestinal Irritability and Painful Injections 847
A. Gastrointestinal irritability 847
B. Avoidance of painful injections 848
VII. Suppressing Undesirable Organoleptic Properties 849
A. Odor 849
B. Taste 850
References 852
Part VIII Development of New Drugs: Legal and Economic Aspects
Section Editor: Bryan G. Reuben 855
42. Discover a Drug Substance, Formulate and Develop It to a Product 857
Bruno Galli and Bernard Fatter
I. Introduction 857
II. Discover the Drug Substance 857
A. Exploratory research (target finding) 858
B. Early discovery program (lead finding) 858
C. Mature discovery program (lead optimization) 858
D. Research-development interface 859
E. Learning experiences 859
III. Defining Experimental Formulations, The Creative Phase 859
A. Basic thoughts on oral formulation 859
B. What is the purpose of a formulation? 859
C. Suggested sequence of activities prior to start formulation 860
D. Biopharmaceutical classification of compounds 861
E. How do we proceed at a practical level? 861
F. Which formulation principles are used? 862
IV. Pharmaceutical Development in Industry 863
V. Fixing The Quality And Develop The Product in A Regulated Environment 865
References 866
43. Drug Nomenclature 867
R. G. Balocco Mattavelli, J.C. Dong, S. Lasseur and S. Kopp
I. Introduction 867
II. Trade Names and Nonproprietary Names 867
III. Drug Nomenclature 868
A. INNs for pharmaceutical substances 868
B. Common names selected by the International Standards Organization (ISO) 874
IV. Use and Protection of Nonproprietary Names 874
A. Use of nonproprietary names 874
B. Protection of nonproprietary names 874
V. Summary 875
References 875
Annex 875
44. Legal Aspects of Product Protection: What a Medicinal Chemist Should
Know about Patent Protection 878
Maria Souleau
I. Introduction 878
A. History of the patent-system prior to 1883 878
B. Main conventions and treaties 879
II. Definition of A Patent - Patent Rights 882
III. Kind of Inventions 882
IV. Subjects of Patents: Basic and Formal Requirements for Filing a Patent 882
A. Basic requirements 882
B. Formal requirements 888
V. Lifetime of Patents 890
VI. Ownership of Patents 890
VII. Infringement of a Patent 890
VIII. Patents as a Source of Information 891
IX. Patenting in the Pharmaceutical Industries 891
X. Conclusion 892
References 892
45. The Consumption and Production of Pharmaceuticals 894
Bryan G. Reuben
I. "Important" Drugs 895
A. The top-earning drugs 895
B. The most widely prescribed drugs 895
C. National differences in prescribing 899
II. Sources of Drugs 902
A. Vegetable sources 902
B. Animal sources 902
C. Biological sources 902
D. Fermentation 903
E. Chemical synthesis 903
III. Manufacture of Drugs 903
A. Good manufacturing practice 904
B. Plant design 904
C. Formulation and packaging-sterile products 905
D. Choice of reagents 906
E. "Green" chemistry 906
F. Downstream processing 907
G. Outsourcing 907
IV. Social and Economic Factors 909
A. Pattern and cost of innovation 909
B. Patents 910
C. Orphan drugs 911
D. Generic Pharmaceuticals 912
E. Parallel trade 914
F. Cost containment measures 914
G. Pharmacoeconomics 916
V. The Future of the Pharmaceutical Industry 918
A. Trends in Pharmaceuticals 919
B. Conclusion 920
References 920
Index 923 |
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| index_date | 2024-07-02T21:43:10Z |
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| spelling | The practice of medicinal chemistry ed. by Camille Georges Wermuth 3. ed. Amsterdam [u.a.] Elsevier, Acad. Press 2008 XXXVI, 942 S. Ill., graph. Darst. txt rdacontent n rdamedia nc rdacarrier Chemistry, Pharmaceutical Drugs Design Models, Chemical Pharmaceutical Preparations chemistry Pharmaceutical chemistry Pharmazeutische Chemie (DE-588)4132158-3 gnd rswk-swf Klinische Chemie (DE-588)4135255-5 gnd rswk-swf (DE-588)4151278-9 Einführung gnd-content Pharmazeutische Chemie (DE-588)4132158-3 s DE-604 Klinische Chemie (DE-588)4135255-5 s Wermuth, Camille Georges Sonstige oth HBZ Datenaustausch application/pdf http://bvbr.bib-bvb.de:8991/F?func=service&doc_library=BVB01&local_base=BVB01&doc_number=016678236&sequence=000002&line_number=0001&func_code=DB_RECORDS&service_type=MEDIA Inhaltsverzeichnis |
| spellingShingle | The practice of medicinal chemistry Chemistry, Pharmaceutical Drugs Design Models, Chemical Pharmaceutical Preparations chemistry Pharmaceutical chemistry Pharmazeutische Chemie (DE-588)4132158-3 gnd Klinische Chemie (DE-588)4135255-5 gnd |
| subject_GND | (DE-588)4132158-3 (DE-588)4135255-5 (DE-588)4151278-9 |
| title | The practice of medicinal chemistry |
| title_auth | The practice of medicinal chemistry |
| title_exact_search | The practice of medicinal chemistry |
| title_exact_search_txtP | The practice of medicinal chemistry |
| title_full | The practice of medicinal chemistry ed. by Camille Georges Wermuth |
| title_fullStr | The practice of medicinal chemistry ed. by Camille Georges Wermuth |
| title_full_unstemmed | The practice of medicinal chemistry ed. by Camille Georges Wermuth |
| title_short | The practice of medicinal chemistry |
| title_sort | the practice of medicinal chemistry |
| topic | Chemistry, Pharmaceutical Drugs Design Models, Chemical Pharmaceutical Preparations chemistry Pharmaceutical chemistry Pharmazeutische Chemie (DE-588)4132158-3 gnd Klinische Chemie (DE-588)4135255-5 gnd |
| topic_facet | Chemistry, Pharmaceutical Drugs Design Models, Chemical Pharmaceutical Preparations chemistry Pharmaceutical chemistry Pharmazeutische Chemie Klinische Chemie Einführung |
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