The Practice Of Medicinal Chemistry

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ForewordThe world’s economy depends to a significant extent on our ability to deliver affordable and sustainablehealthcare. As such, this new edition of The Practice of Medicinal Chemistry plays an important role in educatingthe next generation of scientists in the area as it goes beyond the simple delivery of new healing drugs to combatdisease and illness. It enriches our knowledge and the very understanding of the lives of everyone on the planet.It is truly amazing how the different scientific disciplines can combine in this way to design and make such awonderful array of functional molecules to serve some of our current needs. Nevertheless, the future presentsenormous healthcare challenges that can only be met by appropriate investment and further fundamental scientific discovery. This new edition of The Practice of Medicinal Chemistry provides a unique scholarly compilation ofthe tools, techniques, and methods necessary to begin this journey of discovery, whether in industry oracademia.The book’s practical overview differentiates this text from others. It provides a menu of topics that can be consulted individually, while also providing a holistic view covering the history of drug discovery through to theissues of today involving the consumption and production of pharmaceuticals. The process of drug discoveryhas become a highly complex operation requiring the medicinal chemist to acquire wide-ranging skills from areassuch as biology, technology, modelling, delivery, physiochemistry, and synthesis. To pull this together in a singlebook is a heroic task that these authors have done magnificently.As our science moves forward toward more biologicals, smaller volume products that are focused on patients,and more sustainable and flexible manufacturing in an ever more regulated environment, we will require newgenerations of creative individuals. They will need to be ever more innovative, using all the tools our modernsociety can offer. In particular, big-data mining, tissue sampling and genomic mapping, the “Internet of Things,”and wearable health monitors will all be likely components in the armory of the next breed of medicinal chemist.I regard this expanded textbook as essential reading for all those new to the field. It also provides a qualitycheck for current practitioners in this rapidly evolving environment. The book also does not shy away from providing a future vision of the trends of the discipline. It is written by experts who elegantly convey their passion,experience, and insight for the benefit of all readers.I therefore welcome this updated and expanded version of The Practice of Medicinal Chemistry and believe itprovides—as did past editions—the bedrock of our discipline.Steven V. LeyCambridgehttp://www.leygroup.ch.cam.ac.uk/xiii

Preface to the Fourth EditionBringing a new drug to patients is both a privilege and a challenge fraught with success and failure. A privilegebecause there can be no greater calling than to alleviate suffering to enable a healthier life.Without health, life is not life; it is only a state of languor and suffering—an image of death. BuddhaA challenge fraught with success and failure as no drug makes it from idea to patients without experiencingsuccess and failure.Success is not final; failure is not fatal. It is the courage to continue that counts. Winston ChurchillProf. Camille Wermuth recognized the need to capture in a single volume the essence of the disciplinesneeded by medicinal chemists, so as to enable those just entering the field or the seasoned professional to keeppace with the ever-changing nature of drug discovery and development. His vision became The Practice ofMedicinal Chemistry, providing the medicinal chemistry community with access to experts from across the industry and academia who would share their knowledge to educate the community, thereby preparing the community to recognize and seize opportunities as they emerged.Fortune favors the prepared mind. Louis PasteurThe fourth edition has built off the previous editions. It is updated to reflect developments over the last sevenyears, including five new chapters on topics such as the evaluation of the biological activity of compounds andsystems biology. More than seventy experts from ten countries have shared their insights and perspectives onthe practice of medicinal chemistry.The editorial work for the fourth edition has been shared by Camille Wermuth, Pierre Raboisson, DidierRognan, and Dave Aldous. Odile Blin helped organize and shape how we initiated the fourth edition; we areindebted to her tireless professionalism. The editors wish to express their thanks to Molly M. McLaughlin andthe Elsevier Academic Press, who have worked with us to keep this project moving forward.I believe my final quote—from Jason Calacanis—captures the challenges medicinal chemists face every day.You have to have a big vision and take very small steps to get there. You have to be humble as you execute but visionary and gigantic in terms of your aspiration. In the Internet industry, it’s not about grand innovation; it’s about a lot of little innovations—every day,every week, every month—making something a little bit better. Jason CalacanisMedicinal chemistry is a highly collaborative and iterative process that has many paths. Being open, collaborative, and humble are qualities that will help you successfully navigate these paths from idea to patient.xv

ContentsList of ContributorsForewordPreface to the Fourth EditionPreface to the Third EditionPreface to the Second EditionPreface to the First EditionVII. Target ValidationVIII. ConclusionReferencesxixiiixvxviixixxxiIILEAD COMPOUND DISCOVERYSTRATEGIESI4. Strategies in the Search for New Lead Compoundsor Original Working HypothesesGENERAL ASPECTS OFMEDICINAL CHEMISTRYCAMILLE G. WERMUTH, BRUNO VILLOUTREIX, SERGE GRISONI,ANNE OLIVIER AND JEAN-PHILIPPE ROCHERI.II.III.IV.V.IntroductionFirst Strategy: Analog DesignSecond Strategy: Systematic ScreeningThird Strategy: Exploitation of Biological InformationFourth Strategy: Planned Research and RationalApproachesVI. Fifth Strategy: Applying Biophysical Technologiesand Computational MethodsVII. ConclusionReferences1. Medicinal Chemistry: Definitions and Objectives,Drug Activity Phases, Drug Classification SystemsPETER IMMINGI. Definitions and ObjectivesII. Drug Activity PhasesIII. Drug Classification SystemsReferences686868378122. Evaluation of the Biological Activityof Compounds: Techniques and Mechanismof Action Studies5. Natural Products as Pharmaceuticals andSources for Lead StructuresIAIN G. DOUGALL AND JOHN UNITTDAVID J. NEWMAN, GORDON M. CRAGG AND DAVID G.I. KINGSTONI. IntroductionII. Drug Discovery Approaches and Screening CascadesIII. In Vitro AssaysIV. Ex Vivo AssaysV. In Vivo AssaysAcknowledgementsReferences15161738394242I. IntroductionII. The Importance of Natural Products in Drug Discoveryand DevelopmentIII. The Design of an Effective Natural-Products-BasedApproach to Drug DiscoveryIV. Examples of Natural Products or Analogues as DrugsV. Future Directions in Natural Products as Drugsand Drug Design TemplatesVI. SummaryReferences3. Drug Targets, Target Identification, Validation,and ScreeningWALTER M.M. VAN DEN BROECKI.II.III.IV.V.VI.IntroductionWhat is a Drug Target?The Purpose of Target IdentificationTarget Options and Treatment OptionsTarget Deconvolution and Target DiscoveryMethods for Target Identification and Validation73747884909396961021021061161281301316. In Silico Screening: Hit Finding fromDatabase Mining454647515354TIAGO RODRIGUES AND GISBERT SCHNEIDERI. IntroductionII. In Silico ScreeningIII. De Novo Designv141143150

viCONTENTSIV. Conclusions and Future DirectionsGlossaryReferences154156156IIIPRIMARY EXPLORATION OFSTRUCTURE-ACTIVITYRELATIONSHIPS7. Fragment-Based Drug DiscoveryVENKATA VELVADAPU, BENNETT T. FARMER AND ALLEN B. REITZI. Ligand Protein Interactions: First PrinciplesII. What is Fragment-Based Drug Discovery?III. Creation and Analysis of FBDD LibrariesIV. Fragment Screening MethodsV. Other Biochemical and Biophysical MethodsVI. Fragment Merging/Linking/GrowingVII. Fragment Hit Follow-Up, and Pitfalls to AvoidVIII. Zelborafs, First Approved Drug from FBDDIX. Limitations of FBDDX. Trends for the 1. Conformational Restriction and StericHindrance in Medicinal ChemistryPETER WIPF, ERIN M. SKODA AND ANDRÉ MANNI. IntroductionII. Case StudiesIII. Summary and OutlookReferences27928529729712. Application Strategies for the PrimaryStructure Activity Relationship Exploration8. Molecular Variations Based on IsostericReplacementsCAMILLE G. WERMUTH, SERGE GRISONI, BRUNO VILLOUTREIXAND JEAN-PHILIPPE ROCHERPAOLA CIAPETTI AND BRUNO GIETHLENI. IntroductionII. History: Development of the Isosterism ConceptIII. Currently Encountered Isosteric and BioisostericModificationsIV. Scaffold HoppingV. Analysis of the Modifications Resulting from IsosterismVI. Minor Metalloids-Toxic IsosteresReferences1811821862202242292339. Ring TransformationsCHRISTOPHE MORICE AND CAMILLE G. WERMUTHI. IntroductionII. Analogical ApproachesIII. Disjunctive ApproachesIV. Conjunctive ApproachesV. ConclusionReferences24324425826026326310. Macrocycles: Under-Explored and PoorlyExploited Drug Class Despite the ProvenTherapeutic PotentialI. IntroductionII. Preliminary ConsiderationsIII. Hit Optimization StrategiesIV. Application RulesReferences30230230331231713. Substituent GroupsPATRICK BAZZINI AND CAMILLE G. WERMUTHI.II.III.IV.V.VI.IntroductionMethyl GroupsEffects of Unsaturated GroupsEffects of HalogenationEffects of HydroxylationEffects of Thiols and Other Sulfur-ContainingGroupsVII. Acidic FunctionsVIII. Basic GroupsIX. Attachment of Additional Binding SitesReferences31932033133834534634935135235414. The Role of Functional Groups inDrug Receptor InteractionsPIERRE RABOISSONLAURENT SCHAEFFERI. Nature as a Source of MacrocyclesII. Identification of Macrocyclic Drugs Using EitherPhenotypic Screen or Target-Based ApproachIII. Macrocycles: The Drugs in the Middle SpaceIV. Effect of the Macrocyclization on Drug-Like PropertiesV. Interaction of Macrocycles with their TargetsVI. Synthesis of Macrocycles & Library EnrichmentVII. ConclusionReferences267268270270271274274274I. IntroductionII. General PrinciplesIII. The Importance of the Electrostatic and StericMatch Between Drug and ReceptorIV. The Strengths of Functional Group Contributionsto Drug Receptor InteractionsV. Cooperative BindingReferences359360360370376377

viiCONTENTS15. Compound Properties and their Influenceon Drug Quality19. Multitarget Drugs: Strategies and Challengesfor Medicinal ChemistsHONGMING CHEN, OLA ENGKVIST AND THIERRY KOGEJRICHARD MORPHY AND ZORAN RANKOVICI. IntroductionII. Compound Drug-Likeness AnalysisIII. Compound PromiscuityIV. Compound ADMET PropertiesV. Ligand Binding Efficiency MetricsVI. Conclusions and Future OutlookReferences37938038238438639039116. Pharmacological Space39539539940540740717. Systems Biology: A New Paradigm for DrugDiscovery449451453465467469470TIM JONCKERSI. IntroductionII. Ritonavir: Rejuvenating a Suboptimal DrugIII. Sildenafil, Side Effects are Not Always BadIV. Nucleotide Prodrugs: Chemical Trojan HorsesV. MiltefosineVI. AztreonamVII. ConclusionsReferences473474477478481483485485VHIBA ABI HUSSEIN, ALEXANDRE BORREL, LESLIE REGAD,DELPHINE FLATTERS, ANNE BADEL, COLETTE GENEIX,MICHEL PETITJEAN, ANNE-CLAUDE CAMPROUX ANDOLIVIER TABOUREAUI. IntroductionII. Drug-Target Space (off-target)III. Systems Biology SpaceIV. Phenotype SpaceV. ExamplesVI. ConclusionReferencesIntroductionStrategies for Lead GenerationMain Areas of Focus in DiscoveryOptimization of the Activity Profile and WiderSelectivityV. The Physicochemical ChallengeVI. SummaryReferences20. Selective Optimization of Side Activities(SOSA) in Drug DiscoveryANDREW L. HOPKINSI. What is Pharmacological Space?II. Chemical SpaceIII. Target SpaceIV. 9413415418418421421IVSUBSTITUENTS AND FUNCTIONS:QUALITATIVE ASPECTS OFSTRUCTURE-ACTIVITYRELATIONSHIPSSPATIAL ORGANIZATION, RECEPTORMAPPING AND MOLECULARMODELING21. Pharmacophore Identification andPseudo-Receptor ModelingGERHARD WOLBER AND WOLFGANG SIPPLI.II.III.IV.IntroductionMethodologyAdvanced ApproachesApplication Study: Novel Histamine H3-ReceptorAntagonistsV. Recent Developments and OutlookVI. ConclusionsReferences48949349750150550750722. Protein Crystallography and Drug Discovery18. Optical Isomerism in DrugsJEAN-MICHEL RONDEAU AND HERMAN SCHREUDERCAMILLE G. WERMUTHI. IntroductionII. Experimental Facts and their InterpretationIII. Optical Isomerism and Pharmacodynamic AspectsIV. Optical Isomerism and Pharmacokinetic AspectsV. Practical ConsiderationsReferences429430435437439444I. Introduction511II. Historical Background512III. Basic Principles and Methods of Protein Crystallography 514IV. Applications527V. Two Selected Examples531VI. Outlook532References533

viiiCONTENTS23. Physiological Aspects Determining thePharmacokinetic Properties of DrugsII. Enhancing Oral BioavailabilityIII. Enhancing Brain PenetrationReferencesKOEN BOUSSERY, FRANS M. BELPAIRE AND JOHAN VAN DE VOORDEI. IntroductionII. Passage of Drugs Through Biological BarriersIII. Drug AbsorptionIV. Drug DistributionV. Drug EliminationVI. Some Pharmacokinetic Parameters and TerminologyVII. Variability in PharmacokineticsFurther Reading53954154254754855255755924. Biotransformation Reactions and their EnzymesBERNARD TESTA AND BERND CLEMENTI.II.III.IV.V.IntroductionFunctionalization ReactionsConjugation ReactionsBiological Factors Influencing Drug MetabolismWhat is the Relative Significance of These ManyTypes of Metabolic Reactions?VI. Concluding RemarksReferences56156357157958058158228. Designing Prodrugs and BioprecursorsYONG MI CHOI-SLEDESKI AND CAMILLE G. WERMUTHI. IntroductionII. The Different Kinds of ProdrugsIII. Practical Applications of Carrier ProdrugsIV. Unique Approaches to Carrier Prodrug DesignV. Bioprecursor Prodrug ExamplesVI. DiscussionVII. Difficulties and LimitationsVIII. ConclusionReferencesCHEMICAL MODIFICATIONSINFLUENCING THEPHARMACOKINETIC PROPERTIES29. Drug Delivery with Organic Solventsor Colloidal Dispersed SystemsANNE-CHRISTINE MACHEREY AND PATRICK M. DANSETTEBERND U. RIEBESEHLHistorical BackgroundIntroductionReactions Involved in Bioactivation ProcessesExamples of Metabolic Conversions Leading to ToxicMetabolitesV. 611611JEAN-MICHEL SCHERRMANNIntroductionBiology and Function of TransportersTransporters in Drug DispositionRoles of Transporters in Drug Pharmacokinetics,Pharmacodynamics and ToxicologyV. ConclusionAcknowledgmentsReferencesI. IntroductionII. Physicochemical Drug PropertiesIII. Oral Drug DeliveryIV. Parenteral Drug DeliveryReferences69970070070472030. Preparation of Water-Soluble Compounds byCovalent Attachment of Solubilizing MoietiesCAMILLE G. WERMUTH AND DOMINIQUE LESUISSE26. Drug Transport Mechanisms and their Impacton the Disposition and Effects of DrugsI.II.III.IV.657658661668686690690691692VI25. Biotransformations Leading to ToxicMetabolites: Chemical . IntroductionII. Solubilization StrategiesIII. Acidic Solubilizing ChainsIV. Basic Solubilizing ChainsV. Nonionizable Side ChainsVI. Concluding RemarksReferences72372472673473974174231. Improving the Water-Solubility of Compounds byMolecular Modification to Disrupt Crystal PackingMINORU ISHIKAWA AND YUICHI HASHIMOTO27. Strategies for Enhancing Oral Bioavailabilityand Brain PenetrationGERHARD GROSSI. Introduction631I. IntroductionII. Rationale for Disruption of Crystal Packing as anAlternative Method to Improve SolubilityIII. Improvement of Solubility by DisruptingIntermolecular Hydrogen Bonds747748749

CONTENTSIV. Improvement of Solubility by Disrupting MolecularPlanarityV. Improvement of Solubility by Bending the MolecularStructureVI. Advantages of Improving Solubility by MolecularModification to Weaken Intermolecular InteractionVII. ConclusionReferences75176076276376432. Chemical and Physicochemical Approaches toSolve Formulation Problems80881981982082035. Web Alert: Using the Internet for MedicinalChemistryDAVID CAVALLAHARVEY LIEBERMAN AND N. MURTI VEMURII. IntroductionII. StabilityIII. BioavailabilityIV. Modifying the Duration of ActionV. Manufacturing IssuesVI. Adapting to Patient’s NeedsReferencesIII. Drug NomenclatureIV. Use and Protection of Nonproprietary NamesV. SummaryReferencesAnnexix76776777478178278378833. Discover a Drug Substance, Formulate, andDevelop It to a ProductPIERRE deMONTIGNY, DAVID HARRIS, CHRIS HO, FRANZ WEIBERTH,BRUNO GALLI AND BERNARD FALLERI.II.III.IV.V.Introduction793The Discovery Phase794Defining Experimental Formulations, the Creative Phase 796Preparation for a New Drug-Product Launch800Conclusion: Drug Discovery and Developmentin ompound InformationBiological Properties of CompoundsDrug InformationPhysical Chemical InformationPrediction and Calculation of Molecular PropertiesChemical SuppliersChemical SynthesisChemoinformatics Software ProgramsChemical AnalysisChemical PublicationsPatent InformationToxicologyMeta-Sites and Technology Service ProviderDatabasesXVII. 3883984184236. Protection of Inventions in MedicinalChemistryRICHARD LUTHI AND CHRISTOPHER BRICEVIIPHARMACEUTICAL AND CHEMICALMEANS TO SOLUBILITY ANDFORMULATION PROBLEMSI.II.III.IV.Patents and the Medicinal ChemistWhat Kinds of Medical Inventions can be Patented?The Basics of Patent LawThe Role of the Medicinal Chemist in the PatentArenaV. Patents as a Source of Scientific InformationVI. Other Forms of ProtectionVII. Conclusion84384584685886086186234. Drug NomenclatureRAFFAELLA.G. BALOCCO MATTAVELLI, JI-CUI DONG, SOPHIE LASSEUR,A. ROMEO AND SABINE KOPPI. IntroductionII. Trade Names and Nonproprietary Names807807Index863

C H A P T E R4Strategies in the Search for New LeadCompounds or Original Working HypothesesCamille G. Wermuth1, Bruno Villoutreix2, Serge Grisoni3, Anne Olivier4and Jean-Philippe Rocher51Founder of Prestwick Chemical, Strasbourg, France; 2Université Paris Diderot Sorbonne Paris Cité, Inserm, Paris,France; 3Pierre Fabre Research Institute, Toulouse, Cédex, France; 4Sanofi-Aventis Recherche et Développement,Chilly-Mazarin, France; 5Pierre Fabre Research Institute, Castres, FranceO U T L I N EI. IntroductionA. Hits and LeadsB. The Main Hit or Lead Finding Strategies737474II. First Strategy: Analog DesignA. Typical ExamplesB. The Different Categories of AnalogsC. Pros and Cons of Analog Design74747676III. Second Strategy: Systematic ScreeningA. Extensive ScreeningB. Random ScreeningC. High-Throughput ScreeningD. Screening of Synthesis IntermediatesE. New Leads from Old Drugs:The SOSA Approach7878798082IV. Third Strategy: Exploitation ofBiological InformationA. Exploitation of Observations Madein Humans8284B. Exploitation of Observations Madein AnimalsC. Exploitation of Observations Made inthe Plant Kingdom and in Microbiology89V. Fourth Strategy: Planned Research andRational ApproachesA. L-DOPA and ParkinsonismB. Inhibitors of the ACEC. Discovery of the H2-Receptor Antagonists90909092VI. Fifth Strategy: Applying BiophysicalTechnologies and Computational MethodsA. Biophysical TechnologiesB. Computational Methods93939488VII. Conclusion96References9685So ist denn in der Strategie alles sehr einfach, aber darum nicht auch alles sehr leicht. (Thus in the strategy everything is very simple,but not necessarily very easy). Carl von Clausewitz [1]I. INTRODUCTIONThis chapter deals with the various strategies leading to active compounds and active compounds collections.The introduction of modern biology methods and technologies has driven the discovery process to a target-basedThe Practice of Medicinal Chemistry.73 2015 Elsevier Ltd. All rights reserved.

744. STRATEGIES IN THE SEARCH FOR NEW LEAD COMPOUNDS OR ORIGINAL WORKING HYPOTHESESapproach. However, the discovery strategies leading to new drugs may also still address systems-basedapproaches such as the phenotypic screening methods [2]. The primary objective is to identify original and attractive starting points for therapeutic discovery programs. Such programs typically begin with the search for “hits.”A. Hits and LeadsA hit is an active substance having a preferential activity for the target and which satisfies all of the followingcriteria [3]: (1) reproducible activity in a relevant bioassay, (2) confirmed structure and high purity, (3) specificityfor the target under study, (4) confirmed potential for novelty, and (5) a chemically tractable structure, that is,molecules presenting a certain affinity for a target.Identifying hits for a new target usually involves screening of a wide range of structurally diverse small molecules in an in vitro bioassay. Alternatively, small molecules can be screened for their potential to modulate a biological process thought to be critical in disease or in which the target is thought to play a major role.Miniaturization and robotics means that the number of compounds that can be screened has greatly increased,and several thousand compounds can be screened in one day.Once a hit is discovered, its activity must be confirmed and validated. Typical hit validation criteria are asfollows: (1) the hit must be active in vitro and be amenable to in vivo activity in target or disease models; (2) the hitshould not display human ether-a-go-go-related (hERG) toxicity; (3) the analogs of the hit must display clearstructure activity relationships (SAR); (4) basic physicochemical and ADME properties of the hit series must beevaluated in order to identify potential unwanted properties in the series and to assess structure propertiesrelationships (SPR); (5) the hit should not contain chemically reactive functions; and (6) the hit must providepatent opportunities. Only then does it becomes a lead substance, commonly named “lead.”If a lead molecule emerges from these additional studies on SAR, absorption, distribution, metabolism, excretion(ADME), and toxicity, it acquires the “clinical drug candidate” status. After a short toxicological study, it fulfills thecriteria required for administration to humans for initial clinical studies.B. The Main Hit or Lead Finding StrategiesA retrospective analysis of the ways leading to discovery of new drugs suggests that five successful strategiescan yield new hits and/or lead compounds [4,5]. The first strategy is based on the modification and improvement of already existing active molecules. The second one consists of the systematic screening of sets ofarbitrarily chosen compounds on selected biological assays. The third approach resides in the retroactive exploitation of various pieces of biological information that sometimes result from new discoveries made in biologyand medicine, and sometimes are just the fruits of more or less fortuitous observations. The fourth route to newactive compounds is a rational design based on the knowledge of the molecular cause of the pathologicaldysfunction. The fifth strategy is based on the structural knowledge of the target combined with computationalmethods or biophysical technologies of ligand protein interaction.II. FIRST STRATEGY: ANALOG DESIGNThe most popular strategy in drug design is the synthesis of analogs of existing active molecules. The objective isto start with known active principles or “first-in-class” drugs and—by various chemical transformations—preparenew molecules (sometimes referred to as “follow-on” or “me-too compounds”) for which an increase in potency, abetter specific activity profile, improved safety, or a better formulation that is easier-to-handle by physicians andnurses or more acceptable to the patient are claimed.A. Typical ExamplesA typical illustration of this approach is found in the series of losartan analogs (Figure 4.1) or in the conazoleseries (Figure 4.2). All the compounds show similar structures and similar affinity for the angiotensin II receptor.As such they can be considered “full” analogs.In the pharmaceutical industry, motivations for analog design are often driven by competitive and economicfactors. Indeed, if the sales of a given medicine are high and the company is found in a monopolistic situation,protected by patents and trademarks, other companies will want to produce similar medicines, with someII. LEAD COMPOUND DISCOVERY STRATEGIES

ClONSHON NNHO2CNKNHO2CNN NNNHNNCO2HLosartanDuPont (1986/1994)EprosartanSmithKline Beecham (1989/1997)ValsartanNovartis (1990/1996)CH3NOONONOON NON NNNHNONNCandesartanTakeda (1990/1999)NNNHNCH3IrbesartanSanofi (1990/1997)OHOTelmisartanBoehringer Ingelheim (1991/1999)FIGURE 4.1 Angiotensin AT1 receptor antagonists derived from losartan. Despite their structural similarity, it can be assumed that thecorresponding discoveries were made independently. The first year under parentheses is the basic patent year; the second one is the year ofthe first n (1968/1971)NNNClOxiconazoleSiegfried (1975/1983)SulconazoleSyntex eJanssen (1977/1981)FFluconazolePfizer (1981/1988)FenticonazoleRecordati nssen (1983/1988)ClSetraconazoleFerrer (1984/1992)FIGURE 4.2 An example of me-too compounds (full analogs) is given by micoconazole-derived fungistatics, which act by inhibition of theergosterol biosynthesis. The first year under parentheses is the basic patent year; the second one is the year of the first launch.

764. STRATEGIES IN THE SEARCH FOR NEW LEAD COMPOUNDS OR ORIGINAL WORKING HYPOTHESESH OHH R 95191NONFIGURE 4.3 Some examples of structural analogs. Despite their structural analogy, these compounds present different pharmacological activities.therapeutic improvements if possible. They will therefore use the already commercialized drug as a lead compound and search for ways to modify its structure and some of its physical and chemical properties while retaining or improving its therapeutic properties.B. The Different Categories of AnalogsThe term analogy, derived from the Latin and Greek analogia, has been used in natural sciences since 1791 todescribe structural and functional similarity [6]. Extended to drugs, this definition implies that the analog of anexisting drug molecule shares chemical and therapeutical similarities with the original compound. This definitionsuggests three categories of drug analogs: (1) analogs presenting chemical and pharmacological similarity;(2) analogs presenting only chemical similarity; and (3) analogs displaying similar pharmacological propertiesbut presenting totally different chemical structures.Analogs of the first category, presenting at the same time chemical and pharmacological similarities, can beconsidered as “full” or “true” analogs (Figures 4.1 and 4.2). These analogs correspond to the class of drugs oftenreferred to as “me-too compounds.” Usually, they are improved versions of a pioneer drug over which theypresent a pharmacological, pharmacodynamic, or biopharmaceutical advantage. Other examples are theangiotensin-converting enzyme (ACE) inhibitors derived from captopril, the histamine H2 antagonists derivedfrom cimetidine, and the hydroxymethyl-glutaryl-CoA reductase (HMG-CoA reductase) inhibitors derived frommevinolin. Such analogs are designed for industrial and marketing reasons with the same justifications as thosewhich are valid for any other industrial products such as laptop computers or automobiles.The second class of analogs, which are made of chemically similar molecules and for which we propose theterm “structural analogs,” contain compounds originally prepared as close and patentable analogs of a novellead, but for which the biological assays revealed totally unexpected pharmacological properties. A historicalexample of the emergence of a new activity is provided by the discovery of the antidepressant properties of imipramine, which was originally designed as an analog of the potent neuroleptic drug chlorpromazine. Observationof an “emergent” activity can be purely fortuitous or can result from a voluntary and systematic investigation.Another example, illustrating that chemical similarity does not necessarily mean biological similarity, is foundfor steroid hormones. Testosterone and progesterone, although being chemically very close, have very differentbiological functions (Figure 4.3). Similarly, minaprine is a dopaminergic drug, whereas its cyano analog SR 95191is a potent MAO-A inhibitor [7].For the third class of analogous compounds, chemical similarity is not observed, but they share common biological properties. We propose the term “functional analogs” for such compounds. Examples are the neuroleptics chlorpromazine and haloperidol or the tranquillizers diazepam and zopiclone (Figure 4.4). Despite different chemicalstructures, they show similar affinities for the dopamine and the benzodiazepine receptors, respectively. The designof such drugs is presently facilitated, thanks to virtual screening of large libraries of diverse structures.C. Pros and Cons of Analog DesignAnalog design lacks originality and has often been a source of criticism of the pharmaceutical industry [10]. Eachlaboratory wants to have its own antiulcer drug, its own antihypertensive, etc. These drug copies are called “me-tooII. LEAD COMPOUND DISCOVERY STRATEGIES

77II. FIRST STRATEGY: ANALOG H3NZolpidemOH3CN CH3FIGURE 4.4 Zopiclone and zolpidem are selective benzodiazepine receptor agonists not related chemically to benzodiazepines [8,9].products.” Generally, the owner firm of the original drug continues to prepare new analogs, to ens

Medicinal chemistry is a highly collaborative and iterative process that has many paths. Being open, collabora-tive, and humble are qualities that will help you successfully navigate these paths from idea to pa

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