The · Practice of Medicinal Chemistry

Third edition

Edited by

Camille Georges Wermuth Prestwick Chemical Inc.

Illkirch, France

AMSTERDAM • BOSTON • HEIDELBERG • LONDON • NEW YORK • OXFORD @ • PARIS • SAN DIEGO • SAN FRANCISCO • SINGAPORE • SYDNEY • TOKYO

Academic Press is an imprint of Elsevier

ELSEVIER , ) ~ ~ .

Biography

Section Editors

Contributors

Preface to the First-Edition

Preface to the Secend Edition

Preface to the Third Edition

Part I General Aspects of Medicinal Chemistry Section Editor: Hugo Kubinyi

I. A History of Drug Discovery Franfois Chast

I. Introduction A The renewal of chemistry

. B. The dawn of the organic chemistry crosses the birth of biology II. Two Hundred Years of Drug Discoveries

A Pain killers: best-sellers and controversies B. Giving back the heart its youth C. Fight against microbes and viruses D. Drugs for immunosuppression E. Contribution of chemists to the fight against cancer E Drugs for endocrine disorders G. Anti-acid drugs H. Lipid lowering drugs I. From neurotransmitters to receptors J. Drugs of the mind Considerations on Recent Trends in Drug Discovery A From genetics to DNA technology B. Hopes and Iimits for drug hunting

References

Chemistry: Definitions and Objectives, Drug Activity Phases, Orug Classification Systems Peter Imming

I. Definitions and Objectives A Medicinal chemistry and related disciplines and terms B. Drugs and drug substances C. Stages of drug development

II. Drug Activity Phases A The pharmaceutical phase B. The pharmacokinetic phase

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C. The pharmacodynamic phase D. The road to successful drug development?

111. Drug Classification Systems A. Classification by target and mechanism of action B. Other classification systems

References

Contents

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3. Measurement and Expression of Drug Effects lean-Pierre Nowicki and Bernard Scatton

73

I. Introduction II. In Vitra Experiments

A. Binding studies B. Ligand-receptor interaction-induced functional effects C. Allosteric interaction D. Expression of functional effects for targets other than GPCRS E. Cellular and tissular functional responses

III. Ex Vivo Experiments IV. In Vivo Experiments

References

4. Molecular Drug Targets lean-Pierre Gies and Yves Landry

73 75 75 76 78 79 79 81 82 83

85

I. Introduction 86 A. How many drug targets for how many drugs? 86 B. From the drug target to the response ofthe organism 86 C. Drug binding, affinity and selecÜvity 87 D. Various ligands for a single target 87

I I. 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 Ior{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 lntrinsic 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 NFr;.B 98 E. Receptors of the cellular adhesion 99

IX. G-Protein-Coupled Receptors 99 A. How many druggable GPCRs? 100

5.

B. Diversity of G-proteins c. Diversity of GPCR-elicited signaling and related drug targets

X. Nuclear Receptors As Drug Targets References

Drug Targets, Target Identification, Validation and Screening Kenton H. Zavitz, Paul L. Barteland Adrian N. Hobden

I. lntroduction

II. 1mproving the Resolution of Disease Etiology II!. Biopharmacuetical Therapies

A. Passive immunotherapy IV. Drug Target ldentification

A. Rare mutations leading to generalized therapies B. Minirig the proteome c. Yeast two-hybrid systems D. RNA interference

V. Hit-to-Lead A. Cell-based screening B. Intracellular receptors c. lntracellular enzymes D. G-protein-coupled receptors E. Transgenie animals F. Drug metabolism G. Toxicology

VI. Clinical Biomarkers VII. Conclusions

II Lead Compound Discovery Strategies Section Editor: John R. Proudfoot .

Strategies in the Search for New Lead Compounds or Original Working Hypotheses Camille G. Wermutn

I. lntroduction A. Hits and Ieads B. The main hit or Iead finding strategies

11. First Strategy: Analog Design A. Typical examples B. The different categories of analogs C. Pros and cons of analog design

111. Second Strategy: Systematic Screening A. Extensive screening B. Random screening C. High-throughput screening D. Screening of synthesis intermediates E. New Ieads from old drugs: The SOSA approach

IV. Third Strategy: Exploitation of Biologicallnformation A. Exploitation of observations made in humans B. Exploitation of observations made in anirnals C. Exploitation of observations made in the plant kingdom and in microbiology

V. Fourth Strategy: Planned Research and Rational Approaches A. L-DOPA and rarkinsonism

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B. Inhibitors of the ACE C. Discovery of the H2-receptor antagonists

VI. Conclusion References

7. High~Throughput Screening and Drug Discovery lohn R. Proudfoot

I. lntroduction II. Historical Background III. From Screen to Lead

A. Compound collections B. Assays C. Hit-to~lead process

IV. Examples of Drugs Derived from Screening Leads A. Reverse transcriptase inhibitors, nevirapine. efavirenz, and delavirdine B. Endothelin antagonists. bosentan, sitaxsentan. edonentan, and ambrisentan C. Raf kinase inhibitor, sorafenib

V. Practical Application, Recent Example A. IKK inhibitors

VI. Conclusion References

8. Natural Products as Pharmaceuticals and Sources for Lead Structures David J. Newman, Gordon M. Cragg and David G. I. Kingston

I. Introduction II. The Importance of Natural Products in Drug Discovery and Development

A. The origin of natural products · · B. The uniqueness of the natural products approach C. The impact of new screening methods

III. The Design of an Effective Natural-Products-Based Approach to Drug Discovery A. Acquisition of biomass ' B. The unexplored potential of microbial diversity C. Extraction D. Screening methods E. Isolation of active compounds F. Structure elucidation G. Further biological assessment H. Procurement of large-scale supplies I. Determination of structure-activity relationships

IV. Examples of Natural Products or Analogs as Drugs A. Antihypertensives B. Anticholesterolemics C. Immunosuppressives D. Antibiotics E. Microbial anticancer agents F. Anticancer agents from plants G. Anticancer agents from marine organisms H. Antimalarial agents I. Other natural products

V. Future Directions in Natural Products as Drugs and Drug Design Templates A. Introduction B. Combinatorial chemistry C. Natural products as design templates D. lnteractions of microbial sourc~s. genomics. and synthetic,chemis~ry

VI. Summary References

Contents

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I 59 160 161 161 162 163 163 164 167 167 168 168 168 168 169 169 169 169 171 171 172 174 175 177 177 177 177 177 178 178 180 180

Biology Oriented Synthesis and Diversity Oriented Synthesis in Compound Collection Development Kamal Kumar, Stefan Wetze! and Herbert Waldmann

I. Introduction-11. Diversity Oriented Synthesis

A DOS: Principles R DOS of small molecule libraries C. Applications of DOS libraries

111. Biology Oriented Synthesis A Introduction R The scaffold tree for structural classification of natural products C. Protein structure similarity dustering D. BIOS: The combined application of SCONP and PSSC K BIOS: Prospects and future directions

IV Conclusion and Outlook References

In Silico Screening: Hit Finding from Database Mining Thierry Langer a~td Sharon D. Bryant

I. lntroduction A Chemoinformatics in drug discovery R What is the difference between a hit and a Iead structure? C. Data mining using chemoinformatics

II. Representation of Chemical Structures A Structural keys and I D fingerprints_ R Topological descriptors C. 3D descriptors D. Further descriptors

111. Data Mining Methods IV Database Searches

A Distance and similarity searches R 2D database searches C. 3D database searches

V Applications A Ligand~based in silico screening R Structure~based in silico screening C. Assessing affinity profiles using parallel in silico screening D. Example: Parallel pharmacophore~based virtual screening

VI. Conclusion and Future Directions References

Fragment~Based Drug Discovery Bennett T. Farmer and Allen R Reitz

I. Ligand-Protein lnteractions: First Principles A Binding energy as the sum of the parts R Historical development C. Ligand efficiency

II. Status of Late 1990s Drug Discovery in the Pharmaceuticallndustry

111. What is FBDD? A Concept and overview B. Differences between FBDD and HTS/HTL approaches C. The rolle of the medicinal ehernist in FBDD

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-X IV. Creation and Analysis of FBDD Libraries

A. Generalevaluation and analysis B. Computational approaches C. Use of primary data: sprouting and merging to create secondary libraries

V. Nuclear Magnetic Resonance A. I D (ligand-based) screening B. Example C. 20 (protein-based) screening

VI. X-ray Crystallography A. General principles and limitations B. Examples

VII. Other Biophysical and Biochemical Screening Methods A. Substrate activity screening B. In situ dick chemistry C. SPR spectroscopy D. SAR by mass spectroscopy

VIII. Methods for Fragment Hit Follow-Up A. How tobest reduce false positives (NMR, MS) and false negatives (X-ray) B. Isothermal and differential titration calorimetry and further secondary analysis

IX. Trends for the Future References

12. Lead~Likeness and Drug~Likeness Alex Polinsky

I. Introduction II. Assessing "Drug-Likeness"

A. Avoiding known threats B. Mirnieking known drugs C. Direct property prediction

III. Selecting Setter Leads: "Lead-Likeness" A. What is a "high-quality" Iead compound? B. Designing "lead-like" libraries for biochemical screening

IV. Conclusion References

13. Web Alert: Using the Internet for Medicinal Chemistry David Cavalla

I. Introduction II. Blogs

III. Wikis A. RSS information feeds

IV. Compound Information A. Chemspider B. The N1H Roadmap and Pubehern C. ChemBank

V. Biological Properties of Compounds A. Prediction of biochemical properties B. Molecular datasets C. Information on metabolic properties

VI. Drug Information A. DrugBank

VII. Physical Chemical Information VIII. Prediction and Calculation of Molecular Properties

IX. Chemical Suppliers

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X. Chemical Synthesis XI. Chemical Software Programs

A. Chemical drawing and viewing software B. Various chemoinformatics software C. Datasets for virtual screening

XII. Analysis XIII. Chemical Publications

A. Journals B. Open access C. Theses

XIV. Patent Information A. Japanese patents

XV. Toxicology XVI. Metasites and Technology Service Provider Databases

Part III Primary Exploration of Structure-Activity Relationships Section Editor: Camille G. Wermuth

Molecular Variations in Homologous Series: Vinylogues and Benzologues Camille G. Wermutft

I. Homologaus Series A. Definition and classification B. Shapes of the biological response curves C. Results and interpretation

II. Vinylogues and Benzologues A. Applications of the vinylogy princjple B. Comments

References·

Molecular Variations Based on Isosteric Replacements Paola Ciapetti and Bruno Gietftlen '

I. lntroduction II. History: Development of the Isosterism Concept

A. The molecular number B. The isosterism concept C. The notion of pseudoatoms and Grimm's hydride displacement law D. Erlenmeyer's expansion of the isosterism concept E. lsoserism criteria: Present conceptions F. The bioisosterism concept: Friedman's and Thornber's definitions Currently Encountered Isosteric and Bioisosteric Modifications A. Replacement of univalent atoms or groups B. Interchange of divalent atoms and groups C. Interchange of trivalent atoms and groups D. Ring equivalents E. Groups with similar polar effects: functional equivalents F. Reversal of functional groups

IV. Scaffold Hopping A. Successful examples of serendipitous scaffold hopping B. Scaffold hopping and virtual screening

V. Analysis of the Modifications Resulting from Isosterism A. Structural parameters B. Electronic parameters C. Solubility parameters D. Anomalies in isosterism

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VI. Minor Metalloids-Toxic Isosters A. Carbon-silicon bioisosterism B. Carbon-boron isosterism C. Bioiso~teries involving selenium

References

16. Ring Transformations Christophe Morice and Camille G. Wermuth

I. Introduction II. Analogical Approaches

A. Analogy by ring opening: open-chain analogs B. Analogy by ring dosure C. Other analogies

111. Oisjunctive Approaches A. Cocaine-derived local anesthetics B. Morphinic analgesics C. Oopamine autoreceptor agonists 0. CCK antagonists

IV. Conjunctive Approaches A. Oopaminergic antagonists B. Glutamate NMOA and AMPA receptor antagonists C. Norfloxacin analogs 0. Melatonin analogs

V. Condusion References

17. Conformational Restrietion and/or Steric Hindrance in Medicinal Chemistry Andre Mann

I. Introduction A. Theoretical points B. On constrainted analogs C. On conformational analysis 0. On the natur of Steric effects E. Rigid compounds and bioavailability

II. Case studies A. Bradykinin B. Allylic constraints for inducing conformational rigidity C. Oiversity-Oriented Synthesis 0. Epibatidine bioactive conformation E. Ligands for the Hepatitis C virus F. Nociceptin G. Opioid receptors ligands H. Peptidomimetics for SH2 domains

111. Summary and Outlook References

18. Homo and Heterodimer Ligands the Twin Drug Approach Jean-Marie Contreras and Wolfgang Sippl

I. Indroduction II. Homodimerand Symmetrical Ligands

A. Symmetry in nature B. Homodimers as receptors ligands C. Homodimers as enzyme inhibitors

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D. Homodimers as DNA ligands E. Homodimers of pharmacological interest

111. Heterodimer and Dual Acting Ligands A. Hybrid molecules as ligands of two different receptors B. Hybrids as enzymes inhibitors C. Hybrids acting at one receptor and one enzyme D. Other examples of dual acting drugs

IV. Binding Mode Analysis of ldentical and Non-identical Twin Drugs A. ldentical and non-identical twin drugs interacting with two adjacent binding sites located

on the same macromolecule B. Identical twin drugs interacting with two similar binding sites located an different

monomers of the same macromolecule C. Identical and non-identical twin drugs interacting with two different binding sites located

on different macromolecules V. Conclusion

References

19. Application Strategies for the Primary Structure-Activity Relationship Exploration Camille G. Wermuth

I. Introduction 11. Preliminary Considerations lll. Hit Optimization Strategies

A. Same information about the target is available B. No information about the target is available C. The predominant objective is potency D. The predominant objective is tne establishment of SARs E. The predominant objective consists of analog design

.IV. Application Rules A. Rule number one: the minor modification rule B. Rule number two: the biologicallogic rule' C. Rule number three: the structurallogic's rule D. Rule number four: the right substituent choice E. Rule number five: the easy organic synthesis (EOS) rule E Rule number six: eliminate the chirat centers! G. Rule number seven: the pharmacologicallogic rule

References

IV Substituents and Functions: Qualitative and Quantitative Aspects of Structure-Activity Relationships Section Editor: Han van de Waterl;Jeemd

Substituent Groups Bazzini and Camille G. Wermuth

l. lntroduction II. Methyl Groups

A. Effects on solubility B. Conformational effects C. Electronics effects D. Effects on metabolism E. Extensions to other small alkyl groups

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III. Effects of Unsaturated Groups A. Vinyl series B. Allylic series C. Acetylenic series D. Cyclenic equivalents of the phenyl ring

IV. Effects of Halogenation A. The importance of the halogens in the structure-activity relationship B. Usefulness of the halogens and of cognate functions

V. Effects of Hydroxylation A. Effects on solubility B. Effects on the ligand-receptor interaction C. Hydroxylation and metabolism

VI. Effects of Thiols and Other Sulfur-Containing Groups A. o·rugs containing thiol B. Drugs containing oxidized sulfides C. Drugs containing thiocyanate or thiourea

VII. Acidic Functions A. Effects on solubility B. Effects on biological activity

VIII. Basic Groups IX. Attachment of Additional Binding Sites

A. To increase lipophilicity B. To achieve additional interactions

References

21. The Role of Functional Groups in Drug.,....Receptor Interactions Laurent Schaeffer

I. Introduction II. General Principles

III. The Importance of the Electrostatic and Steric Match Between Drug and Receptor A. Electrostatic interactions B. Steric interactions C. Enthalpy/entropy compensation

IV. The Strengths of Functional Group Contributions to Drug-Receptor Interactions A. Measuring functional group contributions B. The methyl group and other nonpolar substituents C. The hydroxyl group and other hydrogen-band forming substituents D. Acidic and basic substituents E. Practical applicatiops for the medicinal ehernist F. Ligand efficiency

V. Cooperative binding References

22. Compound Properties and Drug Ouality Christopher A. Lipinski

I. Introduction li. Combinatorial Libraries

A. Library design for HTS screens B. Experimental synthesis success rate C. Poor solubility and library design D. Importance of the synthesis rate-determining step E. If protocol development is rate determining F. Poor ADME properties - business aspects

Contents

441 442 443 445 447 448 448 451 452 453 453 453 454 454 454 454 456 456 457 458 459 459 459 460

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XV--G. If library production is rate determining 484 H. Relative importance of ADME assays 484

111. Chemistry Contra[ 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 Contra[ 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. ln Vitra Potency and Chemistry Control 487 A. Lead complexity 487

VI. Metabolie 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. lntroduction to OSAR' 491 II. Brief History and Outlook 492

111. OSAR 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 autoOSAR 503 E. Experimental design 504 F. Inverse OSAR 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

510

V Spatial Organization, Receptor Mapping and Molecular Modeling Section Editor: David J. Triggle 515

Overview: The Search for Biologically Useful Chemical Space 517 David I. Triggle

I. Intraduction 517 II. How Big is Chemical Space? 518

lll. Biological Space is Extremely Small 518 IV. Limited Biological Space as an Effective Biological Strategy 519

References 520 ~' ~

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25. Pharmacological Space Andrew L. Hopkins

I. What is Pharmacological Space? II. Chemical Space

A. Drug-like space III. Target Space

A. Druggability B. Structure-based druggability C. Degrees of druggability D. Druggable genome

VI. Conclusions Acknowledgments References

26. Optical lsomerism in Drugs Camille G. Wermuth

I. Introduction II. Experimental Facts and Their Interpretation

A. Stereoselectivity in biologically active compounds B. The three-point contact model C. Diastereoisomers D. Stereoselectivity ratios E. Pfeiffer's rule

III. Optical Isomerism and' Pharmacodynamic Aspects A. Differences in potency and antagonism between two enantiomers B. Differences in the pharmacological profile of two enantiomers

IV. Optical Isomerism and Pharmacokinetic Effects A. Isomer effects on absorption and distribution B. Isomer effects on metabolism C. Isomer effects on uptake D. Isomer effects on excretion

V. Practical Considerations A. Racemates or enantiomers? B. The distomer counteracts the eutomer C. Racemic switches D. The distomer is metabolized to unwanted or toxic products E. Deletion of the chiral center F. Usefulness of racemic mixtures

References

27. Multi~ Target Drugs: Strategiesand Challenges for Medicinal Chemists Richard Morphy and Z. Rankovic

I. Introduction II. Strategies for Lead Generation III. Main Areas of Focus in DML Discovery (I 990-2005)

A. SERT-plus DMLs for depression B. Dopamine D2-plus DMLs for schizophrenia C. DMLs targeting the angiotensin system for hypertension D. Histamine H 1-plus DMLs for allergies E. AChE-based DMLs for Alzheimer's disease F. PPAR-based DMLs for metabolic disease G. DMLs that inhibit multiple kina~es for treating cancer

Contents

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H. DMLs targeting the arachidonic acid cascade I. Mu-opioid-plus DMLs for treating pain

IV. Optimization of the Activity Profile and Wider Selectivity V. The Physicochemical Challenge

VI. Summary References

Pharmacophore Identification and Pseudo~Receptor Modeling Wolfgang Sippl

I. Introduction A. Historkai background B. Definitions C. lmportance of the pharmacophore concept D. Application of pharmacophores

II. Methodology A. Pharmacophore modeling

111. Advanced approaches A. Structure-based pharmacophores B. Pseudo-receptor models

IV. Application study A. Pharmacophore-based screening for novel histamine H3-receptor antagonists B. Pharmacophore determination process C. Pharmacophore-based screening of compound libraries

V. Conclusions References

3D Quantitative Structure-Property Relationships Thierry Langer.and Sliaron D. Bryant

I. Introduction II. 3D OSAR Workflow

' 111. 3D OSAR: Conformation Analysis and Molecular Superimposition IV. Calculation of 3D Molecular Field Descriptors V. Statistkai Tools

VI. Alignment Independent 3D OSAR Techniques VII. Validation Of 3D OSAR Models VIII. Applications

A. 3D OSAR study on the structural requirements for inhibiting AChE B. 3D OSAR as a tool to determine molecular similarity

IX. Conclusions and Future Directions References

Protein Crystallography and Drug Discovery lean-Micliel Rondeau and Herman Sclireuder

I. Presentation II. Historical Background

A. The early days of crystallography B. The current state of the art C. Past and present contributions to drug discovery

III. Examples A. Aliskiren (Tekturna™, Rasilez™) B. Nilotinib (Tasigna™)

IV. Basic Principles and Methods of Protein Crystallography A. Crystallization

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B. Data collection C. From diffraction intensities to a molecular structure D. Information content and limitations of crystal structures

V. Practical Applications A. Target identification, selection and validation B. Hit/lead generation C. Lead optimization

References

615 615 618 621 621 623 627 629

Part VI Chemical Modifications Influencing the Pharmacokinetic Properties Section Editor: Richard B. Silverman 635

31. Physiological Aspects Determining the Pharmacokinetic Properties of Drugs Koen Boussery, Frans M. Belpaire and Johan V an de Voorde

I. Introduction II. Passage of Drugs Through Biological Barriers

A. Transcellular drug transport B. Paracellular drug transport

111. Drug Absorption A. Dosage form of the drug B. GI motility and gastric emptying C. GI permeability to the drug D. Perfusion of the GI tract and the first-pass effect

IV. Drug Distribution A. Plasma protein binding B. Drug accumulation C. The blood-brain barrier

V. Drug Elimination A. Excretion B. Biotransformation

VI. Some Pharmacokinetic Parameters and Terminology A. Plasma concentration-time curve B. Valurne of distribution C. Clearance D. Elimination half-life (T112)

E. Bioavailability VII. Variability in Pharmacokinetics

A. Genetic factors B. Age C. Drug interactions D. Disease state E. Pregnancy

Bibliography

32. Biotransformation Reactions and their Enzymes Bernard Testa

I. Introduction II. Functionalization Reactions

A. Enzymes catalyzing functionalization reactions B. Reactions of carbon oxidation and reduction C. Oxidation and reduction of N- and S-containing moieticrs D. Reactions of hydration and hydrolysis

637

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Conjugation Reactions A. Introduction B. Methylation C. Sulfonation D. Glucuronidation E. Acetylation F. Conjugation with coenzyme A and subsequent reactions G. Conjugation reactions of glutathione

IV. Biological Factors Influencing Drug Metabolism V. Concluding Remarks

References

33. Biotransformations Leading to Toxic Metabolites: Chemical Aspects Anne-Cnristine Macnerey and Patrick M. Dansette

I. Historical Background II. Introducnon III. Reactions Involved in the Bioactivation Process

A. Oxidation B. Oxidative stress C. Reduction D. Substitutions: hydrolysis and conjugation E. Eliminations F. Further biotransformations leading to the ultimate toxicant

IV. Examples of Metabolie Conversions Leading to Toxic Metabolites A. Acetaminophen B. Tienilic acid C. Halothane D. Valproic acid E. Troglit.azone

V. Conclusion References

Drug Transport Mechanisms and their Impact on the Disposition and Effects of Drugs Jean-Micnel Scnerrmann

I. lntroduction II. Biology and Function of Transporters

A. Modes of active transpoft B. Genes and classification C. Basic structure D. Distributions and properties of transporters in tissues

III. Transporters in Drug Disposition A. ABC tr.ansporters B. SLC transporters

IV. Roles of Transporters in Drug Pharmacokinetics, Pharmacodynamics and Toxicology A. Intestinal absorption B. Liver and hepatic clearance C. Blood barriers and tissue distribution D. Kidney and renal clearance

V. Conclusion Acknowledgments References

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-XX 35. Strategies for Enhancing Oral Bioavailability and Brain Penetration

Brian C. Sliook and Paul F. lackson

I. Introduction II. Enhancing Oral Bioavailability

A. Metabolie stability B. Structural rigidity c. PKa D. Hydrogen bond interactions E. Miscellaneous

111. Enhancing Brain Penetration A. Metabolie stability B. PKa C. LqgP D. Hydrogen bond interactions

IV. Conclusion References

36. Designing Prodrugs and Bioprecursors Camille G. Wermutli

I. Introduction li. The Different Kinds of Prodrugs

A. Definitions and classifications B. The carrier prodrug principle C. The bioprecursor-prodrug principle D. Other categori~s of prodrugs E. Practical applications of prodrug design

li I. Carrier Prodrugs: Application Exatriples A. Improvement of the bioavailability and the biomembrane passage B. Site-specific delivery C. Prolonged duration of action

IV. Particular Aspects of Carrier Prodrug Design A. Use of cascade prodrugs B. Codrugs c. Softdrugs D. Carrier prodrugs: conclusion

V. Bioprecursor Prodrugs: Application Examples A. Oxidative bioactivations B. Reductive bioactivations c. Mixed bioactivation mechanism D. Reactions without change in the state of oxidation

VI. Discussion A. Bioprecursors versus carrier prodrugs B. Existence of mixed-type prodrugs

VII. Difficulties and Limitations VIII. Conclusion References

Part VII Pharmaceutical and Chemical Means to Solubility and Formulation Problems Section Editor: Michael J. Bowker

37. Preparation of Water~Soluble Compounds through Salt Formation Micliael I. Bowker and P. Heinricli Stalil

I. Introduction II. The Solubility of Compounds in Water

Contents

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A. The determination and prediction of solubility B. Ionization of drugs and the importance of pKa

Ill. Acids and Bases Used in Satt Formation IV. Early satt formation studies

A. Choic~ of salt formers B. Prediction of the pH of the salt in solution C. Search for crystalline salts

V. Camparisan of Different Crystalline Salts A. Melting point B. Aqueous solubility C. Common ion and indifferent electrolyte effects D. Hygroscopicity E. Solubility in co-solvents (water-miscible solvents) F. Dissolution Rate G. Partide size and crystal morphology H. Polymorphism and pseudopolymorphism I. Chemical stability J. Other properties

VI. lmplications of Salt Selection on Drug Dosage Forms A. Tablet products B. Hard gelatine capsules C. Parenteral solutions D. Oral solutions E. Suspension formulations F. MDI products G. DPI products H. Softgelatine capsule formulations I. Emulsions, creams and ointments ·

VII. Conclusion References

Preparation of Water~Soluble Compounds by Covalent Attachment of Solubilizing Moieties Camille G. Wermuth

I. Introduction II. Solubilization Strategies

A. How will the solubilizing moiety be grafted? B. Where will it be grafted? C. What kind of solubilizing chain will be utilized?

III. Acidic Solubilizing Chains A. Direct introduction of acidic functions B. Alkylation of OH and NH functions with acidic chains C. Acylation of OH and NH functions with acidic chains

IV. Basic Solubilizing Chains A. Direct attachment of a basic residue B. Bioisosteric exchange of a basic functionality C. Development of a water-soluble prodrug of diazepam D. Attachment of the solubilizing moiety to an alcoholic hydroxyl E. Attachment of the solubilizing moiety to an acidic NH function F. Attachment of the solubilizing moiety to a basic NH2 function G. Attachment of the solubilizing moiety to carboxylic acid functionalities

V. Non-ionizable Side Chains A. Glycolyl and glyceryl side chains B. Polyethylene glycol derivativ~s l· _

C. Glucosides and related compounds

., ,/II' /

xxi

750 751 751 753 753 754 755 755 756 756 758 758 759 759 760 760 761 761 762 762 763 763 763 763 764 764 764 764 765 765

767

767 768 768 768 768 769 769 769 770 775 775 776 776 777 779 779 780 780 780 781 781

-xxii

VI. Concluding Remarks References

39. Drug Solubilization with Organic Solvents, or Using Micellar Solutions or Other Colloidal Dispersed Systems Michaeli. 8owker and P. Heinrich Stahl

I. lntroduction II. Factars Controlling Solubility and Absorption

A. The nature of drug substances 8. The polarity of the solvent system

lll. Water-cosolvent systems IV. Solubilization Mediated by Surfactants V. Solubilization by Lipid Vehicles

A. Emulsions and microemulsions 8. Liposomes

VI. Nanopartkies and Other Nanocolloidal Technologies VII. Drug Delivery and Clearance Mechanisms of Nanocolloids

Vlll. Drug Delivery and Accumulation Using Colloidal Systems for the Treatment of Cancer A. Liposome formulations 8. Fbrmulations based on nanoparticles, microparticles and conjugated systems

IX. Modiflcation of Drug Taxicity by Nanocolloidal Drug Delivery Systems References

40. Improvement of Drug Properties by Cyclodextrins Kaneto Uekama and Fumitqshi Hirayama

I. lntroduction II. Pharmaceutically Useful CyDs

A. Physicochemical proflies of CyDs 8. 8iological proflies of CyDs

111. lmprovement of Drug Properties A. Solubilization 8. Stabilization in solution C. Control of solid properties D. Release cantrot E. Enhancement of drug absorption F. Reduction of side~effects G. Use in peptide and protein drugs H. Combined use of CyDs with additives

IV. CyD~8ased Site~Specifl~ Drug Delivery A. Colon targeting 8. Cell targeting C. 8rain targeting

V. Conclusion References

41. Chemical and Physicochemical Approaches to Solve Formulation Problems Camille G. Wermuth

I. lntroduction II. lncreasing Chemical Stability

111. lmproved Formulation of Peptides and Proteins IV. Dealing with Mesomorphic Crystalline Forms V. lncreasing the Melting Point

A. Salt or complex formation B. Covalent derivatives

Contents

782 783

786

786 788 788 788 789 793 798 798 802 803 806 807 807 808 808 809

813

813 813 814 814 816 817 818 819 821 822 824 826 829 831 832 834 835 835 835

841

841 841 844 845 846 846 846

C. Introduction of symmetry VI. Gastrointestinal Irritability and Painful lnjections

A. Gastrointestinal irritability B. Avoidance of painful injections

VII. Suppressing Undesirable Organoleptic Properties A. Odor B. Taste

References

Part VIII Development of New Drugs: Legaland Economic Aspects Section Editor: Bryan G. Reuben

42. Discover -a Drug Substance, Formulate and Develop It to a Product Bruno Galli and Bemard Faller

I. Introduction II. Discover the Drug Substance

A. Exploratory research (target finding) B. Early discovery program (Iead finding) C. Mature discovery program (Iead optimization) D. Research-development interface E. Learning experiences

111. Defining Experimental Formulations, The Creative Phase A. Basic thoughts on oral formulation B. What is the purpese of a formulation? C. Suggested sequence of activities prior to .start formulation D. Biopharmaceutical classification of compounds E. Ho_w do we proceed at a practicallevel? F. Which formulation principles are used?

· IV. Pharmaceutical Development in Industry V. Fixing The Ouality And Develop The Product•in A Regulated Environment

References

Drug Nomenclature R. G. Balocco Mattavelli, J.C. Dong, S. Lasseurand S. Kopp

I. Introduction Trade Names and Nonproprietary Names Drug Nomenclature A. INNs for pharmaceutical substances B. Common names selected by the International Standards Organization (ISO) Use and Protedion of Nonproprietary Names A. Use of nonproprietary names B. Protection of nonproprietary names

V. Summary References

Legal Aspects of Product Protection: What a Medicinal Chemist Should Know about Patent Protection Maria Souleau

I. Introduction A. History of the patent-system prior to 1883 B. Main conventions and treaties

xxiii --

847 847 847 848 849 849 850 852

855

857

857 857 858 858 858 859 859 859 859 859 860 861 861 862 863 865 866

867

867 867 868 868 874 874 874 874 875 875 875

878

878 878 879

--• xxiv

I!. Definition of A Patent - Patent Rights Ill. Kind of Inventions IV. Subjects of Patents: Basic and Formal Requirements for Filing a Patent

A. Basic requirements B. Formal requirements

V. Lifetime of Patents VI. Ownership of Patents VII. Infringement of a Patent VIII. Patents as a Source of Information

IX. Patenting in the Pharmaceutical Industries X. Conclusion

References

45. The Corisumption and Production of Pharmaceuticals Bryan G. Reuben

I. "Important" Drugs A. The top-earning drugs B. The most widely prescribed drugs C. National differences in prescribing

II. Sources of Drugs A. Vegetable sources B. Anima! sources C. Biological sources D. Fermentation E. Chemical synthesis

Ill. Manufacture of Drugs A. Good manufacturing practiCe B. Plant design C. Formulation and packaging-sterile products D. Choice of reagents E. "Green" chemistry F. Downstream processing G. Outsourcing

IV. Social and Economic Factars A. Pattern and cost of innovation B. Patents C. Orphan drugs D. Generic pharmaceuticals E. Parallel trade F. Cost containment measures G. Pharmacoeconomics

V. The Future of the Pharmaceutical Industry A. Trends in pharmaceuticals B. Conclusion

References

Index

Contents

882 882 882 882 888 890 890 890 891 891 892 892

894

895 895 895 899 902 902 902 902 903 903 903 904 904 905 906 906 907 907 909 909 910 911 912 914 914 916 918 919 920 920

923