Welcome to Week 1

Starting week one video

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Chapter 1 PreRegulatory Medicine
Introduction to Chapter 1
Chapter1containsthreesubsections.
NaturalProducts
SyntheticDrugs
NeedforRegulation
Attheconclusionofthischapter,youshouldhaveanappreciationforthetypesofdrugsthathave
beenusedthroughouthistoryanduptothelate1930s.Youshouldalsounderstandthechallenges
facedbydrugregulatoryagenciesastheytrytoenforcethecreationofasafeandeffectivedrug
supply.
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1.1 Natural Products
Ephedrine video
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Pharmacophores in drugs
Background:Thephenethylaminecompoundsmentionedinthevideoarerelativelysmallstructures
withaneasilyidentifiedpharmacophore.Pharmacophoresindrugscanbeconsiderablymore
complex.

Instructions:Readthepassageconcerningcompoundsthatcontainthesamepharmacophore
elementsasmorphine.Usetheinformationtoanswerthequestionsthatfollowthetext.
LearningGoal:Toexamineamolecule'sstructureanddeterminewhetheramoleculecontainsa
specifiedpharmacophore.
Opiates,Opioids,andTheirPharmacophores
Anotablenaturalproductthatcanbetracedtotheearlyhistoryofhumankindismorphine
(1).Morphineisfoundinopium,theresiduethatseepsfromdamagedpoppyseedpods.Morphine
isacomplexalkaloidwithverypotentanalgesic(painrelieving)properties.Beyondofferingpain
relief,morphineisalsohighlyaddictive.

Morphineisnottheonlycompoundfoundinopium.Opiumcontainsapproximatelytwodozen
othercompoundsincludingcodeine(2).Morphineandcodeinearebothknownasopiates.Opiates
arenaturallyoccurringcompoundsthatsharethesameactivityasmorphine.

Anumberofcompoundssimilartomorphineandcodeinecanbesynthesizedinalab.Someare
preparedbymodifyingmorphineitself.Examplesofsyntheticandsemisyntheticmorphine
analoguesincludeheroin(3)andmethadone(4).Theseunnaturalcompoundswithmorphinelike
activityarecalledopioids.Methadonelooksverylittlelikemorphine,butitisstillconsideredan
opioidbecauseofitsbiologicalactivity.

Almostallopiatesandopioidssharecommonstructuralfeaturesknownasthemorphinerule.The
morphinerulestipulatesthestructuralrequirementsforacompoundtohavemorphinelike
activity.Specifically,themorphinerequiresacompoundtohave(1)abenzenering(2)attachedtoa

quaternarycarbonconnectedby(3)atwocarbonspacerto(4)atertiaryamine.Thesestructural
elementsdescribethepharmacophoreofmorphine.

Thepharmacophorecoresofheroinandmethadoneareshownbelowtracedinblue.

Collectivelytheopiatesandopioidsplayakeyroleinpainmanagement.Becauseoftheiraddictive
properties,opiatesandopioidsarenotsuitableforlongtermuse.Forcertainsituations,suchas
postoperativesurgerypain,theyareveryeffectiveandsafe.
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Regulation of herbal dietary supplements?
Background:Manyherbalmedicineshavebeenusedforthousandsofyearsandcontinuetobe
usedtoday.Theherbalmedicine,orherbalsupplement,industryisverylooselyregulatedinthe
UnitedStatesaswellasmostnations.
Instructions:ReadthelinkedarticlebelowfromBMCMedicineconcerningthequalityofherbal
supplementsinthemarketplace.Usetheinformationinthearticletoanswerthequestionsthat
follow.
LearningGoal:understandpurityissueswithintheherbalsupplementindustry.
ArecentarticleinBMCMedicinereportedthatpossiblyahighpercentageofherbalsupplements
containlittleornoneofthesupposedactiveplantmaterial.
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1.2 Synthetic Drugs

Sulfa drugs video
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Early synthetic drugs
Background:Aroundthemiddletolate1800s,organicchemistryhadadvancedsufficientlytoallow
thepreparationoforganicmoleculesasdrugs.
Instructions:Readthepassageoftextbelowonthreeveryearlysyntheticdrugs.
LearningGoal:Togainexposuretotheearlyimportantsyntheticpharmaceuticals.
Belowarethreeveryearlysyntheticdrugs.
chloralhydrate
Chloralhydrate(1)isasolidformedbythereactionoftrichloroacetaldehydeandwater.The
compoundisapotentsedative.Onceitspropertieswerediscoveredaround1870,chloral
hydratewasusedwidelyinmedicine.Chloralhydratewaspronetoabuse,andsolutionsof
chloralhydratebecamecalled"knockoutdrops"ora"MickeyFinn".Thephrase"sliphima
Mickey"becamesynonymouswithusingchloralhydratetoincapacitateapersonforignoble
ends.

aspirin
Aspirin(2)wasfirstpreparedaround1900byascientistatBayer.Itisaneffectiveanalgesic,
antipyretic(reducesfever),antiinflammatory,andanticoagulant(reducesbloodclotting).The
nameAspirinisstillundertrademarkprotectioninsomepartsoftheworld.Inthose
jurisdictionsthegenericformofthecompoundisreferredtoasacetylsalicylicacid,orASA.

phenobarbitol
Phenobarbitol(3)isananticonvulsant.Phenobarbitolwasdiscoveredaround1900duringa

flurryofearlyresearchintheareaofbarbituratesasanticonvulsantsand
sedatives.Phenobarbitolcontinuestobeusedwidelytoday,especiallyinlessdeveloped
nations.

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Pharmacophore of sulfonamide antibiotics
Background:Sulfanilamideistheparentmoleculeofthesulfadrugclass.Thesimplestructureof
sulfanilamideverynearlydescribesthepharmacophoreofthesulfadrugs.
Instructions:Readthetextbelowandusetheinformationtoanswerthequestionsonthe
pharmacophoreofsulfadrugs.
LearningGoal:Toidentifysulfonamideantibioticsbasedupontheirstructuralfeatures.
Asanearlyclassofdrugs,sulfonamideantibioticshavebeenextensivelyexplored.Literally
thousandsofdifferentsulfonamideswerepreparedandtestedinthe1930sand1940s.Through
thesestudies,thepatternofactivityandpharmacophoreforsulfonamideantibioticsbecameclear.
Thepharmacophoreforsulfonamides(1)consistsofa4aminosulfonamidecorewithtolerancefor
arylandacylgroupsonthesulfonamidenitrogen.Almostallsulfonamideantibioticsfollowthis
simplemodel.

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1.3 Need for Regulation
Elixir Sulfanilamide tragedy video
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Continued issues with diethylene glycol

Background:Since1938theUSFoodandDrugAdministrationhasheldincreasedpowersof
oversightoverthesafetyandeffectivenessofpharmaceuticalsintheUnitedStates.Thedrug
regulatoryagenciesofothernationsholdverysimilarrolesandpowers.
Instructions:ReadthetextbelowandtheaccompanyingreportfromtheWorldHealthOrganization
andanswerthesubsequentquestions.
LearningGoal:Tounderstandthecomplexitiesandrisksthatinternationaltradecreatesfordrug
regulatoryagenciestryingtomaintainasafedrugsupply.
DiethyleneglycolplayedadeadlyroleintheElixirSulfanilamidetragedy.Unfortunatelydiethylene
glycolcontinuestobefoundinmedicinesdespitetheeffortsofdrugregulatoryagencies.In2006
manypeople,likelyseveralhundred,diedinPanamaaftertakingcoldmedicinecontaining
diethyleneglycol.
ReadthelinkedbulletinfromtheWorldHealthOrganizationandanswerthequestionsbelow
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Chapter 2 Drug Discovery: From Concept to Market

Introduction to Chapter 2
Chapter2containsthreesubsections.
Phenotypevs.TargetBasedDrugDiscovery
DrugDevelopmentOutline
IntellectualProperty
Attheconclusionofthischapter,youshouldunderstandthedifferentstagesofdevelopmentfora
drug.Youshouldalsoknowthedifferencebetweengenericandbrandeddrugsaswellastheroleof
patentsindrugdiscovery.
2.1 Phenotype and TargetBased Drug Discovery
Phenotype vs. target video
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Mixing target and phenotype
Background:Intheirtraditionalforms,targetbaseddrugdiscoverytendstorelyuponinvitro
testingforleadoptimization,andphenotypebaseddrugdiscoveryleansuponinvivotesting.
Instructions:Readthepassagebelowonhowphenotypebaseddrugdiscoveryprogramsoften
blendwithtargetbasedtechniques.
LearningGoal:Tounderstandthatdifferentapproachestodrugdiscoverycanfrequentlyblur
together.
Astrengthforphenotypebaseddrugdiscoveryisthatthecompoundsofinterestareknowntobe
activebecausetheiractivityhasalreadybeenobservedinalivingorganism.Therelianceoninvivo
testing,however,isasignificanthindranceforphenotypebaseddrugdiscovery.Theinvivotests
aremoreinvolvedandlongerthaninvitrotests,andtheleadoptimizationprocessisslowerasa
result.
Amoreidealsituationwouldbetostartwithacompoundwithknowninvivoactivityandtheability
tooptimizeitspotencywithquickinvitroscreens.Thisidealsituationisacrossbetween

phenotypeandtargetbaseddrugdiscoveryandmostoftenbeginswiththephenotypemodeland
switchesovertothetargetmethod.
Thephenotypemodelbeginswithanobservedeffectinvivo.Thecompoundthatcausestheeffect
istheleadmolecule.Insteadofcontinuingtheprogramwithimprovingtheleadwithmoreinvivo
testing,thedrugdiscoverygroupworkstodiscovertheproteintowhichthemoleculebindsinthe
body.Inotherwords,thediscoverygroupseeksoutthetargetresponsibleforthebiological
activity.Oncethetargetisknown,amolecularbiologygroupwillattempttodevelopabiochemical
bindingassaytotesttheabilityofamoleculetobindthetarget.Newlypreparedcompoundsare
thentestedwiththerapidinvitrobindingassay.
Inthisblendedmodel,thediscoverygroupcanbemoreconfidentthatthefinalmoleculewillhave
activityinanimals.Additionally,theimprovementoftheactivityoftheleadwillbeaccelerated
becauseitisbeingaccomplishedwithinvitromethods.Whenperformedproperly(noteasy!),the
blendedapproachcancombinethebestofbothdrugdevelopmentmethods.Drugprogramsthat
discovertheirleadsthroughphenotypebasedobservations,regardlessofhowtheylateroptimize
thelead,aretypicallycategorizedasphenotypebaseddiscoveryprograms.
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Support for phenotypebased drug discovery
Background:Thetopicsofphenotypeandtargetbaseddrugdiscoverycanbeverydivisive.Both
methodsofdrugdevelopmenthaveveryvocalsupportersanddetractors.Therehasrecentlybeen
apushforarenewedemphasisonphenotypebasedmethods.
Instructions:ReadlinkedarticlefromScienceBusinesseXchangeandanswerthesubsequent
questions.
LearningGoal:Togainanappreciationandunderstandingforphenotypebaseddrugdiscoveryina
medicinalchemistrycoursethatwillemphasizetargetbaseddrugdiscovery.
ArecentarticleinScienceBusinesseXchangediscussesdevelopmentsinphenotypebaseddrug
discovery.
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2.2 Drug Discovery Outline

Drug discovery outline video
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The cost of doing business
Background:Thetotalcostofbringingadrugtomarketishighlydebated,butthemostreliable
estimatesseemtoplacethefigureataroundUS$1billionorhigher.
Instructions:Readthetextbelowandusetheinformationtoanswerquestionsinasubsequentunit.
LearningGoal:Tolearnaboutthecostofthedifferentstagesofdrugdevelopment.
AccordingtoDiMasietal.,
1
thecostsofadrugcanbebrokendownasshownbelow.

Notethatthepreclinicalstagesofdrugdiscovery,whichcantakeyears,onlyaccountfor
approximatelyonequarterofthetotalcosts.Theexpensesbegintoaccruequicklywiththeclinical
trials.PhaseIIItypicallycoststhemostbecauseoftheverylargenumberofpatientsinvolved.In
PhaseIandPhaseII,volunteersandpatientsareintenselymonitored.ThecostsofPhaseIand
PhaseIImightbelowerthanPhaseIII,buttheperpatientcostsarehigherintheearlyphases.
1. DiMasi,J.A.;Hansen,R.W.;Grabowski,H.G.ThePriceofInnovation:NewEstimatesofDrug
DevelopmentCosts.J.HealthEcon.2003,22,151185.
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The risk of failure

Background:Mostattemptstodevelopadrugendinfailure.Sincethecostsofbringingadrugto
marketarehigh,evenfailuresintheearlystagesofadrugprogramaddsignificantcoststoadrug
company.
Instructions:Readthetextbelowandusetheinformationtoanswerquestionsinasubsequentunit.
LearningGoal:Tolearnaboutthedifferentreasonsforfailuresindrugdevelopment.
Awidelymentionedstatisticisthat,forevery10,000compoundsthatareanalyzedinadrug
discoveryprogram,only5willbetestedinhumansasclinicalcandidates,andonly1willbe
approvedasadrug.Theoriginofthesefiguresishardtotrace,butwecanmakeanattempt.Ina
targetbaseddrugdiscoveryprogram,itwouldnotbeuncommontoscreenamillionormore
moleculesinalibrary.Perhapsthetop1%intermsofbindingtothetargetmightbeselectedashits
inthescreen.Thatcutoffwouldgive10,000hits.Ofthese10,000compounds,5(following
optimization)mightbeadvancedtotheclinicwithjust1becomingadrug.
AccordingtoDiMasietal.,
1
theprimaryreasonsforfailureofadrugdiscoveryeffortintheUnited
Statesfrom1981to1992arelistedbelow.Thesefigureswouldbeforleadsthatmakeitintoanimal
testing.

DiMasifurthergivesthefailureratesforcompoundsthatmakeitintothedifferentclinicaltrials.
Notethatthefailureratesarecumulative.Therefore,aclinicalcandidatehasa29%offailurein
PhaseI.IfitclearsPhaseI,itthenhasa57%offailureinPhaseII.

Onewaytoexaminethisbargraphistoconsidertheprobablyforsuccessofadrug.Ifaclinical
candidatehasa29%chanceoffailinginPhaseI,thenithasa71%chanceofsuccessinPhaseI.
Similarly,itwillhavea43%and76%chanceofsuccessinPhaseIIandPhaseIII,respectively.With
thisinterpretation,adrugwillhavea23%(0.710.430.76)chanceofcompletingallthetrials.A
23%chancecorrespondstosomewherebetweena1in4or1in5chanceofsuccess.
1. DiMasi,J.A.RisksinNewDrugDevelopment:ApprovalSuccessRatesforInvestigationalNew
Drugs.Clin.Pharmacol.Ther.2001,69,297307.
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Questions on cost and failure
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2.3 Intellectual Property
Patents and branding video
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Composition of matter in action

Background:Patentsareatypeofintellectualproperty.Whiletheyareinvaluabletothedrug
industryfortheexclusiverightstheyafford,patentsarelegallyverycomplex.
Instructions:Readthepassagebelowforoneexampleofhowthecompositionofmatterpatentis
usedinthedrugindustry.
LearningGoal:Tolearnaboutcompositionofmatterpatentsandcrystalpolymorphs.
CrystallinePolymorphsofRanitidine
1

Drugsarenormallyprotectedwithacompositionofmatterpatent.Surprisingly,somedrugsrequire
multipledifferentcompositionofmatterpatents.Multiplepatentsareneededwhenadrugexistsin
multiple,differentcrystallineforms.Thesedifferentformsarecalledpolymorphs.
Inpolymorphsthesamemoleculecanpacktogetherindifferentorientationsandpatterns.Each
patternisadifferentpolymorph.Asimpleexampleofpolymorphscanbefoundwithbricks,which
canbestackedinvariouspatternsaspavers.Afewpatternsareshownbelow.Moleculescanstack
indifferentpatternsinmuchthesamefashion.

Becausepolymorphscanhavedifferentphysicalproperties(e.g.,solubilityandmeltingpoint),a
drugcompanymustbeabletocontrolwhichpolymorphofadrugisbeingsynthesized.
Ranitidine(1)isadrugthattreatsacidreflux.In1978Glaxo,thediscovererofranitidine,obtaineda
compositionofmatterpatentonthecompound.Atthetime,thetermofpatentswas17yearsfrom
thedateofissue.Therefore,Glaxo'spatentonranitidinewassettoexpirein1995,or17yearsafter
1978.

AsGlaxocontinuedtoresearchranitidine,asecondpolymorphwasdiscovered.Glaxoobtaineda
compositionofmatterpatentonthesecondpolymorph,calledForm2,in1985.TheForm2patent
wouldexpirein2002.
GlaxoultimatelymarketedranitidineasForm2underthenameofZantac.Duringthe1980sZantac
wasablockbusterdrug,anditssuccesscontinuedintothe1990s.
Around1990acompanycalledNovopharm,agenericdrugmanufacturer,startedtodevelopa
genericformofranitidine.NovopharmhopedtocapitalizeonForm1ofranitidinebecausethe
patentonForm1wouldexpirein1995.Duringtheirresearch,chemistsatNovopharmtriedto
maketheoriginal,Form1polymorphofranitidinebasedontheGlaxoprocedures.Totheirsurprise,
theNovopharmchemistscouldonlyprepareForm2.NovopharmreasonedthatifForm2was
knownallthewaybackin1978inthefirstworkonranitidine,thenthe1985Form2patentwasnot
valid.NovopharmpushedaheadandappliedtotheFDAtomarketgenericranitidinein1995,
correspondingtotheexpirationoftheForm1(perhapsForm2)patent.
GlaxothensuedNovopharmforplanningtomarketranitidine'sForm2,onwhichGlaxohelda
patentuntil2002.AthirdpartylabwascalledintoprepareForm1ofranitidinefromGlaxo's1978
Form1patent.ThelabsuccessfullyreproducedtheproceduretomakeForm1,andGlaxowonthe
case.
NovopharmwentbacktoworkandmanagedtoreproducetheForm1procedure.Novopharmthen
filedpaperworkwiththeFDAtomarketgenericranitidine(Form1)startingin1995,theyearof
expirationofGlaxo'sForm1patent.
GlaxoagainsuedNovopharm.Thistime,GlaxoclaimedthatNovopharm'sForm1ofranitidinelikely
containedimpuritiesofForm2.Ifso,thenmarketingthismixturewouldviolateGlaxo'sexclusive
rightstoForm2.NovopharmprovidedevidencethattheirranitidinewasfreeofForm2,and
Novopharmwonthecase.
1. Bernstein,J.PolymorphismandPatentsfromaChemist'sPointofView.InHilfiker,R.
(Ed.)Polymorphism:InthePharmaceuticalIndustry.Weinheim,Germany:WileyVCH,2006,
Chapter14.
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Global complications with patents
Background:Theinterpretationandimplementationofpatentlawvariesfromonecountryto
another.
Instructions:ReadthelinkedarticlefromTheEconomistandanswerthesubsequentquestions
relatedtopatents.

LearningGoals:Tounderstandhowpatentsaffectdrugprofitabilityaroundtheworld.
ArecentpostingonthewebsiteofTheEconomistcoversakeypatentrulinginIndia.
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