Wermuth’s The Practice of Medicinal Chemistry

Wermuth’s The Practice of Medicinal Chemistry

(Parte 1 de 9)

The Practice of Medicinal Chemistry

Edited by

CAMILLE GEORGES WERMUTH,P HD, PHARMD Founder of Prestwick Chemical, Strasbourg, France

DAVID ALDOUS,B SC,D PHIL Boston Head Lead Generation to Candidate Realisation, Boston, MA, USA

PIERRE RABOISSON,P HD, PHARMD Janssen Infectious Diseases and Diagnostics BVBA, Beerse, Belgium

DIDIER ROGNAN,P HD, PHARMD Laboratoire d’Innovation Therapeutique, CNRS-Universite de Strasbourg, Illkirch, France

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Contents

List of Contributors Foreword Preface to the Fourth Edition

Preface to the Third Edition Preface to the Second Edition

Preface to the First Edition xi xiii xv xvii xix od

1. Medicinal Chemistry: Definitions and Objectives, Drug Activity Phases, Drug Classification Systems

I. Definitions and Objectives 3 I. l)nig Activity Phases 7

Ill. Dn1g Classification Systems 8 References 12

2. Evaluation of the Biological Activity of Compounds: Techntiques and Mechanism of Action Studies

I. Introduction 15 I. l)nig Discovery Approoches ;md Scn.-ening Cascades 16 Ill. /ti Vi1ro Assays 17 IV. Ex Vivo Assays 38 V. In Vivo A$53ys 39

Ackflowledgemenrs 42 References 42

3. Drug Targets, Target ldencification, Validation, and Screening

I. Introduction 45

I I. What is a Drug T3rget! 46

Ill. The Purpose of Targel ldemification 47 IV. Targd Options and T reatmcnl Options 51

V. Target Deconvolution and T:trger Discovery 53 VI. Methods for Target Identification a1\d Validation 54

Vil. Target Validation VIII. Conclusion References

6S 6S

4. Strategies in the Search for New Lead Compounds or Original Working Hypotheses

CAMllU 0. WERMlJTH, 6RVNO VIUOUTREIX. SERO£ ORISON I, ANNE OLIVIER AND JEAN.PHIUPPE ROCt-iER

I. Introduction

I. First Srraccgy: Analog Design

Ill. Second Strategy: SyscemaLic Scree-ning IV. Third Strategy: Exploita11on of Biological Information

V. Fourrh Strategy: Plannt.-d RcSC:trch and Rational

Approaches

VI. Fifth Applyinr: and Computational Methods

Vil. Conclusion References

5. Natural Products as Phannaceuticals and Sources for Lead Scructurcs

DAVJD J. NEW~GORDON M. CRAGG AND DAVJD G.l. KINGSTON

I. Introduction 102 I. The lmport:.mce of Narural Products in Orug Oiscovery and Development I 02

Ill. The Design of an Effective Natural-ProducllV&scd Appronch ro Drug l)iscovcry 106

IV. Examples of Natural Products or Analogues as 01\lgs 116

V. Future Direclions in Natural Products as Drug:s Orug Design Templates I 28 VI. Summary 130 References 131

6. In Silico Screet\ing: Hit Finding from Database Mining

TIAOO RODRIGUES AND OISBERT SOiNElDER

I. lnlroduction 141 I. In Silico Screening 143 Ill. De Novo Design 150 vi CONltNTS Conclusions and Future Directions 154 I G I ry 156 156 PRIMARY EXPLORATION OF

7. Fragment-Based Drug Discovery RELATIONSHIPS VEN KATA VELVADAPU. BENNETT T. FARMER ANO ALLEN B. REITZ

I. Lii:an<l-Protcin Interactions: Fir.st Principles 162 1. Conformational Restriction and Steric l I. What is Fragment·B;;ised On'l: Discovery! 164 Hindrance in Medicinal Chemistry Ill. Creation and Analysis of FBDD Libraries 166 IV. Fras:ment Screenins:; Methods 167 PETER Wlf'F, ERIN M. SKOl)A ANO ANnRt MANN V. Orhcr Biochemical and Merhocls 171 I. Introduction 279 VI. Fragmem Merging/Linking{Growing 172 VI. Fragment Hat Follow-Up, and Pirfalls 10 Avoid 174 I. Case Snidies 285 VIII. Zdborafli, First Approved Dnag from FBDD 175 Ill. Summary and Outlook 297

IX. Limitations of FBDD 176 References 297 X. Trends for the Future 176

References 177 12. Application Strategies for the Primary

8. Molecular Variations Based on lsostcric Structure-Activity Relationship Exploration

Replacements CAMllil C. WERMlJTI I, SERCE CRISONI, BRUNO VILLOUTR£1X

AND JEAN.PHILll'f'E ROCHER

PAOLA CIAl'F.TTI ANO l\RUNO GIETiiLF:N I. Introduction 302

I. l nrroduction 181 I. Preliminary Considerations 302 I. Hist()()•: Development <>f the IS06terism Concept 182 Ill. Hie Optimization Sr.rategies 303 Ill. Currently Encountered lsosteric and Bioisosteric IV. Application Rules 312

Mocliflcarions 186 References 317 1 V. Scaffold Hopping 220 V. Analysis of che Modifications Resulcing from lsoscerism 224

VI. Minor Mc:ralioids-Toxic lsostcrcs 229 13. Substituent Groups

References 233 PATRICK 6A72fNI ANDCAMll.lEO. Wl:RMUTll

9. Ring Transformations !. lnmxlucrion 319 I. Methyl Groups 320

CHRISTOPI 1.E MORia; ANO C'\MIW G. WERMlJTH Ill. Effecc.s of Uruaturatc:<l ~ 331

I. lntr0duction 243 IV. f!ffects of l lalogcnation 338 I. Analogical Approaches 244 V. Effeccs of Hydrox1'latio1\ 345

Ill. Disjunctive Approaches 258 VI. Effeccs ofThiols and Other Sulfur-Containing Conjunctive Approaches 260 Groups 346 Conclusion 263 VI I. Acidic Funcrions 349

References 263 VIII. Basic Groups 351 IX. Attachment of Additional Binding Sites 352

References 354

10. Macrocycles: Under-Explored and Poorly

Exploited Drug Class Despite the Proven Therapeutic Potential 14. The Role of Functional Groups in

PIERRE RABOISSON Drug-Receptor Interactions

LAURENT SCHAEFFER I. Nature as a Source of t->focrocycles 267

I. ldentiftcarion of Macrocyclic Drugs Using Either I. lncroduction 359 Phcnotypic Screen or T.<trgct-Bascd Approach 268 l I. General Principles 300

Ill. Macrocycles The Ona.gs in the Middle Space 270 Ill. The Importance of rhe ElectTosrnric and Steric rv. Effect of the Macrocydization on Drug-Like Properties 270 Macch Between Drug and Receptor 360 v. lmcraction of Macrocyclcs with their Tarticts 271 IV. The Strcni:,oths of Functional Group Contributions

VI. Synthesis of Macrocycles & Library Enrichment 274 to Orug-Receptor Interactions 370

VII. Conclusion 274 V. Cooperalive Binding 376 References 274 References 377

15. Compound Properties and cheir Influence on Drog Quality

HONGMINC CHEN. 01.A ENCKVIST ANO THIERRY KOGEJ

I. Introduction l. Comp<mnd Dnig-Likcne."-< Analysis 1. Compound

IV. Compound ADMET Properties V. Liwind Binding Efficiency Metrics

\I. Conclusions ::ind Future Ouclook ~

16. Pharmacological Space ANOREW L HOPKINS

I What is Phannacological S1'.'Qccl IL Chcmic:1l Space 1. Target Space IV. Conclusion.. Acknowledgments References

17. Systems Biology: A New Paradigm for Drug Discovery

HIRA Alli HLSSEIN. AU:XANDRE llORREL, LESLIE RECAO. DELPHINE Fl.ATIERS. ANNE MOEL. O)l.FJTE GENEIX.

MICllEL l'i;11TJF.AN. ANNE-<-'LAllllE CAMrROUX ANll OLIVIER TAllOUREAU

I. lnrroducrion I. Drug·Targec Sp::ice (off·uirgcc)

1. Systems Biolog)' Space IV. Phcnorype Space

V. Examples VI. Conclusion

References

CONTENTS vii

19. Mulricargec Drug : Strategies and Challenges for Medicinal Chemises

379 I. lntroducrion 449 380 I. Strategies for Lead Gcnernrion 451

382 Ill. Mam AnY<l> of Focus in Dbcovery 453

384 IV. 0pLillll!.iti<)I\ ..if the AcLiviL\' Profile a"d 386 Sclcccivtr)' 465

390 V. The Physicochemical Challenge 467 391 VI. Summary 469 References 470

20. Selective Optimization of Side Activities (SOSA) in Drug Dise<wcry

395 TIM JONCl<F.RS 395

I. lntr0<foccion 399 473 405 I. Ritonnvir: Rcjuvcnanng a Suliophmal Drug 474

407 1. Sildcnafil, Sid..-Effects art Not Always BaJ 477

407 IV. Nucleotide Prodnig;: Chemic.1 Trojan 478 V. Milccfosinc 481

VI. Amcomun 483

VII. C",onclustcms 485

References 485

SPATIAL ORGANIZATION, RECEPTOR }vlAPPING AND MOLECULAR :~ MODELING

418 418 21. Phannacophore Identification and

421 Pseudo-Receptor Modeling 421 OERHMO WOLl\El\ ANI) \'(l()Lf'CANO s1r•PL

I. lnlTOduction

I. Merhodology Ill. Advanced Approaches

SUBSTITUENTS AND FUNCTIONS: IV. Application Smdy: Novel Hisramine Hi-Receptor A nrngo1\iscs 501

18. Optical Isomerism in Drugs CAMILl.E G. Wf.RMUTI I

I. I nrroduccion I. Experimenral focts and their lmerprerncion

1. Optical lwmerism am! PhttrmacoJyn:11ic Aspcctll

IV. Opcic::il Isomerism and Ph:irm3cokinccic Aspects Proccical Considcrocions Rcforc11ces

V. Rccem l:Nvelopmems and Oudook \I. Conclusions

2. Protein Crystallogn1phy and Drug Discovery JEAN·MICllEL RONDEAU AND HERMAN SCllREUDER

I. lmroduCLion 511

429 I. Historical Background 512 430 Ill. l\'l.<ic Principles and Methods of Prorcin Cr,•stallogrnphy 514

435 IV. Applications 527 437 V. Two Selected Examples 531

439 VI. Outlook 532 4 References 533 viii CONltNTS

23. Physiological Aspecrs Determining rhe Pharmacokinetic Properties of Drugs

I. lnmxluction 539 1. PRssnge of Dn1gs Through Biologiclll !Xtrriers 541 I. Drug AL"60rp!ion 542

IV. Drug Oisuiburion 547 V. Drug Elimination 548 VI. Some Pharmacokineric Parame1ers and Terminology 552 VII. Variabilit:y in Pharmacokinetics 557 Furthc:r 559

24. Biotransformation Reactions and their Enzymes BERNARD TESTA AND BERND CUM ENT

I. lntroduc1ion I. FunctionalizRtion Rcnc.tions

Ill. Conjugation Reac1ions IV. Biological Faccors Influencing Drug Mecabolism

V. What is the Relative Significance of These Many

Types of Mecabolic Rcacrions? VI. Concluding Remarks

References

25. Biotransformations Leading to Toxic Metabolites: Chemical Aspects

ANNIU:l MAO IERE\" AND PATRICK M. DANSCTIE

I. Enhancini:; Oral Bioava1labiliLy Ill. Enhancing Brain Penetration References

28. Designing Prodrugs and Bioprecursors YO:-JG Ml Cl!Ol-SUDESKI AND CAMILLE G. WERMUTll

I. Introduction I. The Differenc Kinds of Prodrugs

Ill. Praclical Applicacions of Carrier Prodrugs IV. Unique Approaches to Carrier Prodrug Dt:sign

\I. Bioprecursor Prodn1g Examples VI. Discussion VII. DifficulLies and LimicaLions VIII. C'..onclusion References

29. Drug Delivery with Organic Solvents or Colloidal Dispersed Systems

BERND U. RlEBESEHL

I. Historical Background 585 I. !turoduc1 ion 699 I. Introduction 586 l !. Physicochemical Drug Properties 700

Ill. Rcnctions Involved in Bionctivation Process<.-s 587 Ill. Oral Drug Delivery 700 IV. Paremeral Drug Delivery 704 IV. Examples of Mecabolic C-Onversion.s Leading 10 Toxic

Mecabolites 599 References 720 Conclusion 608 Acknowlcdgmen!s

References

611 61 J 30. Preparation of Water-Soluble Compounds by

26. Drug Transporc Mechanisms and their Impact on the Disposition and Effects of Drugs

I. lntToduction 615 I I. Biology and Function o( T nmsporrcrs 616

Ill. T ransporcers in Drug Disposi!ion 620 Roles of Transporters in Drug PharmMcokinctics,

Pharmacodynamics and Toxicology 624 Conclusion 628

Acknowlcdgmems 628 References 628

27. Strategies for Enhancing Oral Bioavailability and Brain Penetration

CER.l IAR.D CROSS

I. I ntTOduction 63 l

Covalent Attachment of Solubilizing Moieties CAMlu..E G. WER.\IUTH AND DOMINIQUE LESUISSE

I. lnrr<Xlucrion I. Solubilizacion Suaregies Ill. Acidic Solllbilizing Chains IV. Basic Solubilizing Chains

V. Nonionizable Side Chains VI. Concluding Remarts

Rdcn:nccs

31. Improving the Water-Solubility of Compounds by Molecular Modification to Disrupt Crystal Packing

.\llNORU ISHIKAWA ANO YUICHI HASHIMOTO

I. Introduction l. Rationale for DisrupLion of Cryscal Packing as an

Ahema1ive Metl1od co Improve Solubilirr

Ill. lmprovemcnr of Solubility by Disrupring lmermolecular Hydrogen Bonds

CONTENTS ix

IV. Improvement of Solubility by Dismpling Molecular

Planariry 751

V. Improvement of Solubility by Bending the Molecular

Structure 760

VI. Advantages of lmproV"ing Solubiliry by Molecular

Modification to Weaken Intermolecular Interaction 762

Vll. Conclusion 763 References 764

32. Chemical and Physicochemical Approaches to Solve Formulation Problems

I. lnrroduction 767 I. Srability 767 1. Bioavsilabiliry 774 IV. Modifying rhe Duration of Action 781 V. Manufacturing Issues 782

\1. Adapting to Patient's Ncc<ls 783 References 7 8

3. Discover a Drug Substance, Formulate, and Develop It to a Product

1'1£RR1l dcMONTIONY, OAVlll I IARRIS, Cl IRIS 110, FRANZ Wll16EITTH, BRUNO OALLI AND BERNARD FALLER

I. lnrroduction 793 I. The Discovery Phase 794

Ill. Defining Experimencal Fonnulacions, che Creative Phase 796 1>reparation for a New Dnrg-Product Launch 8CO

V. Conclusion: Dn1g Disco"ery and !Xvelopment in Industry 801 Reference 802

34. Drug Nomenclature

RAFFAaLA.O. 81\LOCCO MATIAVEl.l, Jl-CUJ DONG, SOPllE 1.ASSEUR, A. ROMEO AND SABINE KOPP

I. I nrroduction

I. Trade Names and Nonproprieta1y 1 ames 807 807

Ill. Drug Nomenclature 808

IV. Use and Protection ofNonproprictary Names 819 V. Summar\• 819 References 820 Annex 820

35. Web Alert: Using the Internet for Medicinal Chem is cry

I. Introduction 825 I. Rlogs 826 1. Wikis 826 IV. Compound Information 827 V. Biologicril Properties of Compunds 829 VI. Dnig Information 831 VII. Physical Chemical lnfonnation 832

VIII. Prt.>diction and Calculation of Moli:cul;u Properties 832

IX. Chemical Suppliers 834 X. Chemical Synthesis 835

XI. Chemoinformatics Software l'mgrnms 836 XII. Chemical Analysis 836 XIII. Chemical Publications 837 XIV. Patent Information 838 XV. Toxicology 839 X\1. Meta-Sites and Technology Service Provider

Databases 841 XVII. Conclusion 842

36. Protection of Inventions in Medicinal Chemistry

RICHARD LUTHI AND CHRISTOPHER llRICE

I. Patents and the Medicinal Chemist I. Whac Kinds of Medical invencion.s can be Patented? I I. The Basics of Patent Law IV. The Role of 1he lvlt:dicinal Chemist it1 the Patent A

(Parte 1 de 9)

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