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Topics in Medicinal Chemistry 11 James R. Empfield Michael P. Clark Editors Reducing Drug Attrition 11 Topics in Medicinal Chemistry EditorialBoard: P.R.Bernstein,RoseValley,USA A.Buschauer,Regensburg,Germany G.I.Georg,Minneapolis,USA J.A.Lowe,Stonington,USA U.Stilz,Malov,Denmark C.T.Supuran,SestoFiorentino(Firenze),Italy A.K.Saxena,Lucknow,India Aims and Scope Drugresearchrequiresinterdisciplinaryteam-workattheinterfacebetweenchemis- try,biologyandmedicine.Therefore,thenewtopic-relatedseriesTopicsinMedicinal Chemistrywillcoverallrelevantaspectsofdrugresearch,e.g.pathobiochemistry of diseases, identification and validation of (emerging) drug targets, structural biology,drugabilityoftargets,drugdesignapproaches,chemogenomics,synthet- ic chemistry including combinatorial methods, bioorganic chemistry, natural compounds, high-throughput screening, pharmacological in vitro and in vivo investigations,drug-receptorinteractionsonthemolecularlevel,structure-activ- ityrelationships,drugabsorption,distribution,metabolism,elimination,toxicol- ogyandpharmacogenomics. Ingeneral,specialvolumesareeditedbywellknownguesteditors. InreferencesTopicsinMedicinalChemistryisabbreviatedTopMedChemandis citedasajournal. Moreinformationaboutthisseriesat http://www.springer.com/series/7355 James R. Empfield Michael P. Clark l Editors Reducing Drug Attrition With contributions by (cid:1) (cid:1) (cid:1) C.G. Jackson A.S. Kalgutkar A.N.R. Nedderman (cid:1) (cid:1) P. Siegl D.K. Spracklin K.W. Ward Editors JamesR.Empfield MichaelP.Clark VertexPharmaceuticals VertexPharmaceuticals Boston Boston Massachusetts Massachusetts USA USA ISSN1862-2461 ISSN1862-247X(electronic) ISBN978-3-662-43913-5 ISBN978-3-662-43914-2(eBook) DOI10.1007/978-3-662-43914-2 SpringerHeidelbergNewYorkDordrechtLondon LibraryofCongressControlNumber:2014956013 #Springer-VerlagBerlinHeidelberg2014 Thisworkissubjecttocopyright.AllrightsarereservedbythePublisher,whetherthewholeorpartof the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation,broadcasting,reproductiononmicrofilmsorinanyotherphysicalway,andtransmissionor informationstorageandretrieval,electronicadaptation,computersoftware,orbysimilarordissimilar methodologynowknownorhereafterdeveloped.Exemptedfromthislegalreservationarebriefexcerpts inconnectionwithreviewsorscholarlyanalysisormaterialsuppliedspecificallyforthepurposeofbeing enteredandexecutedonacomputersystem,forexclusiveusebythepurchaserofthework.Duplication ofthispublicationorpartsthereofispermittedonlyundertheprovisionsoftheCopyrightLawofthe Publisher’s location, in its current version, and permission for use must always be obtained from Springer.PermissionsforusemaybeobtainedthroughRightsLinkattheCopyrightClearanceCenter. ViolationsareliabletoprosecutionundertherespectiveCopyrightLaw. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publicationdoesnotimply,evenintheabsenceofaspecificstatement,thatsuchnamesareexempt fromtherelevantprotectivelawsandregulationsandthereforefreeforgeneraluse. While the advice and information in this book are believed to be true and accurate at the date of publication,neithertheauthorsnortheeditorsnorthepublishercanacceptanylegalresponsibilityfor anyerrorsoromissionsthatmaybemade.Thepublishermakesnowarranty,expressorimplied,with respecttothematerialcontainedherein. Printedonacid-freepaper SpringerispartofSpringerScience+BusinessMedia(www.springer.com) Preface Thepremiseofthisbookistoprovideguidancetothosepersonswhoarededicated to the creation and development of new drugs to aid patients. Our aim was to address the key factors that have led to failure of preclinical and clinical drug candidates.Despitethesignificantscientificadvancesoverthepastfewdecadesin the disciplines associated with research and development (R&D), the overall productivity, as measured by new approved drugs, has not improved. However, the reasons for failure in the clinic have changed over time. Today the two most prevalentfactorsleadingtodrugfailurearedrugsafetyandlackofefficacy.While clinical failure due to pharmacokinetic factors has been reduced, it is still a significantchallengeattimeswithinthedrugdiscoveryphase.Althoughthesuccess rate in delivering important drugs to patients has not yet yielded significant improvements,ourunderstandingofwhatcausesthesefailuresandhowtoaddress themhasadvanced. Thisvolumedoesnotaimtocoverallaspectsofdrugfailurebutratherfocuses onafewkeyareasthatcanaddressthesuccessratesinpharmaceuticalR&Dfrom theselectionofthebiologicaltargettothesafetyprofilingofthepotentialclinical candidates.Inchapter“TargetSelectionandValidationinDrugDiscovery”,Clive G. Jackson tackles the importance of biological target selection and validation including strategies for prioritizing the most appropriate targets for disease inter- vention. He addresses aspects ofthe complexityofdisease mechanisms,selection of targets in the genomic era, and challenges of clinical trial designs. He also conveys strategies for reducing attrition based on target selection. In chapters “Optimizing Pharmacokinetic Properties and Attaining Candidate Selection” and “The Role of Biotransformation Studies in Reducing Drug Attrition” the authors deal with pharmacokinetic aspects of drug discovery. In chapter “Optimizing Pharmacokinetic Properties and Attaining Candidate Selection”, Keith W. Ward focusesonpharmacokineticrelatedattritionandhowtooptimizethesepropertiesin drug candidates with both in vitro and in vivo studies. In chapter “The Role of Biotransformation Studies in Reducing Drug Attrition”, Douglas K. Spracklin et al. address the key issue of biotransformation and its role in drug attrition, including reactive metabolites. Chapter “Reducing Drug Attrition: Safety v vi Preface Pharmacology”focusesonthekeyroleofsafetypharmacologyintheidentification ofpotentialnewdrugs.PeterSiegeldiscusseshowtomaximizesafetypharmacol- ogyactivitiestoreducedrugattrition. Itisourhopethatthereaderswillfindthisbookhelpfulintheirdrugdiscovery effortstofightagainstdiseases. We would like to thank the authors who have contributed to this treatise for sharingtheirexpertiseaswellasthetimetheydedicatedtothecompletionofthis volume. Boston,MA,USA JamesR.Empfield Introduction Attrition: The Biggest Enemy of the Pharmaceutical Industry The Problem Theresearchanddevelopment(R&D)costsassociatedwithanewdrug(NME:new molecularentity)havegrownsignificantlyoverthepastcoupleofdecades.Astudy undertaken by the US Congressional Budget Office in 2006 found that total spending on health-related R&D had tripled between 1990 and 2006 while NME approvals, following a spike in the mid-1990s had been constant in the range between20and30[1].A2003analysisbyagroupatTuffsUniversityfoundthat the R&D costs associated with new drugs are estimated to be $802 million [2]. However,thisisalowestimatewhentakingintoaccountthetotalcost(allattrition) inR&D.Thecostofdevelopingnewdrugshasbeencalculatedtobegrowingatan annualrateof>13%overthepast60yearsandincreasingatanexponentialrate[3]. A major cause of this increase has been the increased failure of drug programs to deliver a marketed drug for therapeutic use [1]. The success rate from potential candidatedrugtoamarketedproducthasbeenestimatedtobebetween4and11% [4]. Considering all attrition, from the start of chemical optimisation in a drug discoveryproject,theoverallsuccessrateisprobablycloserto1–2%.Thereasons forattritionhavechangedovertime.Withtheintroductionofdrugmetabolismand pharmacokinetics(DMPK)asprimaryscreensindrugdiscoveryprojectssincethe 1990s, pharmacokinetics (poor bioavailability or metabolism) is no longer the primary reason for failure. Instead, toxicity now accounts for the bulk of pre- clinical project and phase I failures. In the later development phases, lack of efficacy is the primary cause of compound attrition. In addition to toxicity and efficacy, portfolio decision-making is a major contributor to attrition. Within the arenaofsmallmoleculedrugdiscoveryanddevelopment,attritionishighestinthe central nervous system (CNS) area and lowest in cardiovascular [5]. Even after market launch, it has been estimated that ~10% of new drugs show unexpected adverse reactions in patients [5]. This book aims to address how drug discovery vii viii Introduction organisationscanimprovesuccessrates(lowerattrition)ontheroadfrompotential biological target for intervention through the creation of candidate drugs and clinicalstudiesandfinallythroughregulatoryapprovalstoaddressunmetmedical needs.Topicscoveredinthisbookarebroad,includingbiologicaltargetselection, medicinalchemistrydesignprinciples,biotransformation,pharmacokineticoptimi- sation,safetypharmacology,toxicology,andpharmaceutics. Advances in Drug Metabolism and Pharmacokinetics (DMPK) and Toxicity Assessment Overthepastcoupleofdecadesthedrugdiscoveryindustryhasplacedanemphasis on frontloading DMPK and toxicity so as to address these areas prior to clinical development.WithintheDMPKareanumerousinvitroassayswithhighthrough- puthavebeendevelopedtoassessdrugcandidatepermeability,metabolicstability, P-glycoprotein(PgP)activetransport,andspecificcytochromeP450inhibitionand metabolism.Inasimilarway,althoughsomewhatmorerecently,invitroassaysto assesstoxicityriskshavebeenestablished.Forexample,assessmentofcardiacrisk of drug candidates is now routinely carried out through various in vitro hERG (human ether-a-go-go gene) evaluations. Similarly, in vitro assessment of genetic toxicityandphosphlipidosis(alipidstoragedisorderthatleadstoexcessaccumu- lation of phospholipids in cells) is carried out at many companies. These assays havenotonlyguidedtheselectionofdrugcandidatesforclinicaldevelopment,but also have enabled a greater understanding of how to design higher quality com- poundsthataredevoidofDMPKandkeytoxicityliabilities.Whilethishashada majorimpactonearlydrugdiscovery,particularlyoppositeDMPK,ithasnonethe- lessonlytouchedthesurfaceofthepotentialtoxicityliabilitiesthatdrugcandidates may face. Therefore, additional efforts to understand how to design more ‘drug- like’agentshavebeenafocusformedicinalchemistsoverthepastdecade. Drug-Likeness, Toxicity and Physical Properties Recentdevelopments,primarilyfromstudiesoflargeproprietaryandpublicdata- bases, strongly indicate that a number of molecular properties are associated with successful DMPK and toxicity drug discovery outcomes, and control of these properties is indicated as a key activity in the war on attrition. The key findings arebrieflysummarisedhere. Thewell-known‘ruleof5’,derivedfromasurveyofdrugsinphaseII[6],has stimulated many further studies aimed at linking these easily assessed physical properties with DMPK and more recently toxicity liabilities. The rule of 5 states that absorption of drugs is optimal when: the molecular weight is <500, Introduction ix lipophilicity(theoctanol-waterpartitioncoefficient,logP)is<5;thesumofoxygen andnitrogenatomsforhydrogenbondacceptorsis<10;andthesumofOHandNH groupsforhydrogenbonddonorsis<5.Lowerlimitswerenotsetinthisanalysis. Thispublishedanalysisbecameaguideformedicinalchemistsanddrugdiscovery scientistsintheireffortstodesigndrugcandidatesthatwouldhaveagreatersuccess rateoppositeDMPKproperties.Sincethisreportin1997,otherphysicalproperties, namely polar surface area (PSA), rotatable bond count, and ionisation state, have been reported to be relevant parameters for bioavailability [6, 7]. The physical propertiesofcompoundsinthevariousphasesofclinicaldevelopmentsuggestthat thereisaconvergencetowardsdrug-likepropertiesascompoundsproceedtowards beingmarketed[8,9].Thisanalysissuggeststhatbothhighermolecularweightand morelipophiliccompounds tendtobediscontinuedfromdevelopmentatahigher rate. Despite this finding, a study on the properties of new compounds being patented in current drug discovery projects indicates that they are both larger (higher MS) and more lipophilic than historically approved oral drugs [10]. Amongst oral drugs, there has also been a substantial increase over time in molecular weight and H-bond acceptors, but lipophilicity, H-bond donors and % PSAarenotchangingsignificantly[11].Ithasbeenproposedthatphysicalproper- ties that are not changing over time are more important indicators of ultimate successandthatlipophilicityisthemostcriticaldrug-likeproperty[10,11]. Recent studies of compounds in differing phases of development show that structuralfeaturesarealsolinkedtosuccessfuloutcomes.IntheGlaxoSmithKline portfolio,thenumberofaromaticringsreducesfrompreclinicaltophaseIIIandit wasproposedthat<3aromaticringsispreferred;however,thearomaticringcount also correlateswith lipophilicity [12]. This is the only report to dateshowingthat attrition in a major pharmaceutical company’s portfolio is linked to compound lipophilicity. The 3-dimensionality of molecules also appears to be important; a simple measure, the fraction of tetrahedral carbon atoms (sp3 hybridised carbon atoms),increasesthroughthedevelopmentphases[13].Asimilartrendwasfound with structural similarity to natural products and metabolites; a ‘biological rele- vance’parameterincreasesthoughthephasesofdrugdevelopment[14]. The importance of optimal drug-like properties has been reinforced by studies relating physicochemical properties to empirical DMPK and toxicity [15] para- meters. Amongst AstraZeneca and Pfizer proprietary compounds, both molecular weight (Mol Wt) and lipophilicity (logD at pH 7.4) influence compound perme- ability in CACO-2 cells [16, 17]. As Mol Wt increases, higher logD is needed to maintainabetterthanevenchanceofreachinghighpermeability[16].Considering permeabilityandmetabolicstabilitytogether,optimalpropertieswerefoundatMol Wt 350 and logD 1.5 [17], values very similar to mean oral drugs [8]; increasing MolWtto>450,however,resultsinamarkedreductionincombinedpermeability andstability[17].InastudyofGlaxoSmithKlineproprietarycompounds,focussing onsolubility,permeability,bioavailability,volumeofdistribution,clearance,PGP efflux, cytochrome P450 inhibition and hERG inhibition, it was found that com- pounds with molecular weight <400 and logP <4 generally had improved risk profiles compared to those with greater values [18]. A study of AstraZeneca

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