Integrated Strategies For Drug Discovery Using Mass Spectrometry

557 Pages·2005·7.723 MB·English

by  Mike S. Lee

JWDD001-Lee-FM JWDD001-Lee May2,2005 17:22 CharCount=0
INTEGRATED
STRATEGIES FOR DRUG
DISCOVERY USING MASS
SPECTROMETRY
MIKES.LEE
MilestoneDevelopmentServices
AJOHNWILEY&SONS,INC.,PUBLICATION
iii
JWDD001-Lee-FM JWDD001-Lee May2,2005 17:22 CharCount=0
INTEGRATED
STRATEGIES FOR DRUG
DISCOVERY USING MASS
SPECTROMETRY
i
JWDD001-Lee-FM JWDD001-Lee May2,2005 17:22 CharCount=0
INTEGRATED
STRATEGIES FOR DRUG
DISCOVERY USING MASS
SPECTROMETRY
MIKES.LEE
MilestoneDevelopmentServices
AJOHNWILEY&SONS,INC.,PUBLICATION
iii
JWDD001-Lee-FM JWDD001-Lee May2,2005 17:22 CharCount=0
Copyright(cid:1)C 2005byJohnWiley&Sons,Inc.Allrightsreserved.
PublishedbyJohnWiley&Sons,Inc.,Hoboken,NewJersey.
PublishedsimultaneouslyinCanada.
Nopartofthispublicationmaybereproduced,storedinaretrievalsystem,ortransmittedinanyformor
byanymeans,electronic,mechanical,photocopying,recording,scanning,orotherwise,exceptas
permittedunderSection107or108ofthe1976UnitedStatesCopyrightAct,withouteithertheprior
writtenpermissionofthePublisher,orauthorizationthroughpaymentoftheappropriateper-copyfeeto
theCopyrightClearanceCenter,Inc.,222RosewoodDrive,Danvers,MA01923,978-750-8400,
fax[phone],oronthewebatwww.copyright.com.RequeststothePublisherforpermission
shouldbeaddressedtothePermissionsDepartment,johnWiley&Sons,Inc.,111RiverStreet,Hoboken,
NJ07030,[phone],fax[phone].
LimitofLiability/DisclaimerofWarranty:Whilethepublisherandauthorhaveusedtheirbesteffortsin
preparingthisbook,theymakenorepresentationsorwarrantieswithrespecttotheaccuracyor
completenessofthecontentsofthisbookandspecificallydisclaimanyimpliedwarrantiesof
merchantabilityorfitnessforaparticularpurpose.Nowarrantymaybecreatedorextendedbysales
representativesorwrittensalesmaterials.Theadviceandstrategiescontainedhereinmaynotbesuitable
foryoursituation.Youshouldconsultwithaprofessionalwhereappropriate.Neitherthepublishernor
authorshallbeliableforanylossofprofitoranyothercommercialdamages,includingbutnotlimitedto
special,incidental,consequential,orotherdamages.
ForgeneralinformationonourotherproductsandservicespleasecontactourCustomerCareDepartment
withintheU.S.at877-762-2974,outsidetheU.S.at317-572-3993orfax317-572-4002.
Wileyalsopublishesitsbooksinavarietyofelectronicformats.Somecontentthatappearsinprint,
however,maynotbeavailableinelectronicformat.
LibraryofCongressCataloging-in-PublicationData:
Integratedstrategiesfordrugdiscoveryusingmassspectrometry/[edited
by]MikeS.Lee.
p. cm.
ISBN-13978-0-471-46127-2
ISBN-100-471-46127-X(cloth)
1.Massspectrometry. 2.Drugs–Analysis. 3.Highthroughputscreening(Drugdevelopment)
I.Lee,MikeS.,1960–
RS189.5.S651552005
615(cid:2).19–dc22 2005003235
PrintedintheUnitedStatesofAmerica
10 9 8 7 6 5 4 3 2 1
iv
JWDD001-Lee-FM JWDD001-Lee May2,2005 17:22 CharCount=0
CONTENTS
Preface ix
ListofContributors xiii
Acknowledgements xvii
1 MiniaturizedFormatsforEfficientLiquid
ChromatographyMassSpectrometry–Based
ProteomicsandTherapeuticDevelopment 01
GaryA.ValaskovicandNeilL.Kelleher
2 Mass-Spectrometry-BasedDrugScreeningAssaysfor
EarlyPhasesinDrugDiscovery 27
MarshallM.Siegel
3 ESI-FTICRasaHighThroughputDrugDiscoveryPlatform 71
KristinA.Sannes-Lowery,LendellL.Cummins,ShuoChen,
JaredJ.Drader,andStevenA.Hofstadler
4 MassSpectrometry–BasedProteomicApproachesfor
DiseaseDiagnosisandBiomarkerDiscovery 95
ThomasP.Conrads,HaleemJ.Issaq,JosipS.Blonder,and
TimothyD.Veenstra
v
JWDD001-Lee-FM JWDD001-Lee May2,2005 17:22 CharCount=0
vi CONTENTS
5 MetabonomicApplicationsinToxicityScreeningand
DiseaseDiagnosis 121
JohnP.ShockcorandElaineHolmes
6 TheCentralRoleofMassSpectrometryinNatural
ProductsDiscovery 149
JeffreyR.Gilbert,PaulLewer,DennisO.Duebelbeis,AndrewW.Carr
7 ApplicationofMassSpectrometrytoCompound
LibraryGeneration,Analysis,andManagement 189
XuehengChengandJillHochlowski
8 ACombinatorialProcessforDrugDiscovery 231
DavidS.Wagner,RichardW.Wagner,FrankSchoenen,
andH.MarioGeysen
9 ApplicationofTechnologicalAdvancesin
BiotransformationStudies 261
CarmenL.Ferna´ndez-Metzler,RajuSubramanianandRichardC.King
10 ApplicationsofMassSpectrometryforthe
CharacterizationofReactiveMetabolites
ofDrugsinDiscovery 289
JimWang,JackWang,MargaretDavis,WilliamDeMaio,
JoAnnScatina,andRasmyTalaat
11 AdvancesinHighThroughputQuantitativeDrug
DiscoveryBioanalysis 315
BradleyL.Ackermann,MichaelJ.Berna,andAnthonyT.Murphy
12 NewStrategiesfortheImplementationandSupport
ofBioanalysisinaDrugMetabolismEnvironment 359
WalterA.Korfmacher
13 AnIntegratedLC-MSStrategyforPreclinical
CandidateOptimization 379
JonathanL.JosephsandMarkSanders
14 NewApproachesforMethodDevelopmentand
PurificationinLeadOptimization 403
YiningZhaoandDavidJ.Semin
JWDD001-Lee-FM JWDD001-Lee May2,2005 17:22 CharCount=0
CONTENTS vii
15 HighThroughputMetabolicandPhysicochemical
PropertyAnalysis:StrategiesandTacticsforImpact
onDrugDiscoverySuccess 433
EdwardH.KernsandLiDi
16 OrganPerfusionandMassSpectrometry 459
C.GeraldCurtis,BenChien,DavidBar-Or,andKumarRamu
17 SamplePreparationforDrugDiscoveryBioanalysis 477
DavidA.Wells
18 Automation 511
JohnD.LaycockandThomasHartmann
Index 543
JWDD001-Lee-FM JWDD001-Lee May2,2005 17:22 CharCount=0
PREFACE
Itcouldbearguedthatdrugdiscoverystrategiesofthepastwereanalogousto
fishingwithalineandhook.Asystematicseriesoftrialanderrorexperiments
suchasquantitativestructure-activityrelationship(QSAR)methodologies,for
example, were commonplace. The process was iterative and labor intensive.
Achemistorbiologisthadrelativelyfewrestrictions,particularlywithtime,
to explore ideas and test hypotheses. The overall endeavor was more craft
thanprocess.
Today’s preference for drug discovery is on high throughput approaches
to accelerate the generation, identification, and optimization of molecules
withdesirabledrugproperties.Alargenumberofsamplesandcorresponding
analyticalmeasurementsarerequiredtomakequickandconfidentdecisions.
Certainly, the need for a faster pace of research is warranted. However, the
currentstrategiesthatemphasizefastcycletimesmakeitappearthatnewdrug
candidates are discovered not with a line and hook approach but harvested
withnets.Thecraftstillremains,butitisoftendifficulttoseeinthemidstof
production-scaleevents.
Fueled by the prospects of a highly efficient drug discovery process and
theneedforanexpandeddrugdevelopmentpipeline,thepharmaceuticalin-
dustryhasaggressivelyembracedtechnologyoverthepastdecade.Medicinal
chemistryhasplayedacentralrolewiththeintegrationofautomatedsynthe-
sistechnologies.Newdrugdiscoveryparadigmsweresubsequentlybornand
thesehighthroughputmedicinalchemistryapproacheshelpedtoserveasthe
gateway for novel biomolecular screening and proteomics techniques. Dur-
ingthistime,highthroughputscreeningapproachesfordrugmetabolismand
ix
JWDD001-Lee-FM JWDD001-Lee May2,2005 17:22 CharCount=0
x PREFACE
pharmacokineticcharacteristicsbecameanessentialpartofthedrugdiscovery
landscape.
The swift integration of highly productive technologies that focused on
samplegenerationcreatedbottlenecksindrugdiscovery.Simplyput,medic-
inalchemistsandtheircollaboratorsweregeneratingsamplesatafasterrate
than they were capable of analyzing them. New formats for automated syn-
thesiscombinedwithafasterpaceofdrugdiscoveryledtoashiftinsample
analysis requirements from a relatively pure sample type to a trace-mixture.
Traditionalmethodsofanalysisbecameantiquated.Newanalyticalstrategies
andtechniqueswerenecessarytomeetsamplethroughputrequirementsand
manpowerconstraints.Technologieswithappropriatesensitivity,selectivity,
andspeedwerequicklyintegratedintomainstreamdrugdiscoveryparadigms
toeffectivelyhandlethepredominantsampletype,atrace-mixture.Drugdis-
covery was forced to become more dependent on technology and become
more agile. Fortunately, scientists became more open about the notion of
usingmassspectrometryasafront-linetoolthroughoutdrugdiscovery.
ThisbookisbasedonaspecialissueofCurr.Top.Med.Chem.publishedin
January2002.Thefocusisprimarilyonmassspectrometry-basedapplications
indrugdiscoverythatrequiretrace-mixtureanalysis.Theselectionoftopicsis
notintendedtobecomprehensive,butratherhighlightthecreativityofanalyti-
calscientistsandtheircollaboratorsthathaveledtocurrentstandardsforanal-
ysisindrugdiscovery.Innovatorsinthefielddescribetheiruniqueperspectives
on integrated strategies for analysis and share future prospects. The topics
represent current industry benchmarks in specific drug discovery activities
thatdealwithproteomics,biomarkerdiscovery,metabonomicapproachesfor
toxicityscreening,leadidentification,compoundlibraries,quantitativebioan-
alyticalsupport,biotransformation,reactivemetabolitecharacterization,lead
optimization, pharmaceutical property profiling, sample preparation strate-
gies,andautomation.
Interestingly,thetraditionaldefinitionandcorefocusofdrugdiscoveryis
still applicable today. A significant change has been the preference for high
throughput approaches and the explosive development of analytical instru-
mentationthatallowsforthefacileinterrogation(qualitativeandquantitative)
of a trace-mixture. Analytical technologies now provide an integral compo-
nentformoderndrugdiscoverypractices.Similartothelocationmantrapre-
scribedinrealestate,thefundamentalmeritsofsensitivityarearequisitefor
high throughput analytical measurements in drug discovery. Due to limited
sample quantities and the need to interrogate compounds of interest at low
concentration,“sensitivity,sensitivity,sensitivity”willmostlikelyremainas
theanalyticalmantraindrugdiscovery.However,highlysensitiveanalytical
platformssuchasmassspectrometerswillcontinuetobenefitfromorthogo-
naltechniquessuchaschromatography,samplepreparation,andinformatics.