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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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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
Pleasewatchtheonlinevideo(7minutes,33seconds).
AcondensedsummaryofthisvideocanbefoundintheVideosummarypage.
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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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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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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
Pleasewatchtheonlinevideo(7minutes17seconds).
AcondensedsummaryofthisvideocanbefoundintheVideosummarypage.
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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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