Prodrugs and Targeted Delivery: Towards Better ADME Properties

507 Pages·2010·4.393 MB·English

by  Raimund Mannhold, Hugo Kubinyi, Gerd Folkers(eds.)

Edited by
Jarkko Rautio
Prodrugs and
Targeted Delivery
Methods and Principles in Medicinal Chemistry
Editedby R. Mannhold,H.Kubinyi, G.Folkers
EditorialBoard
H.Buschmann, H.Timmerman, H.van de Waterbeemd, T.Wieland
Previous Volumes of this Series:
Smit,MartineJ./Lira,SergioA./Leurs, Todeschini,Roberto/Consonni,Viviana
Rob(Eds.) Molecular Descriptors
Chemokine Receptors as Drug
for Chemoinformatics
Targets
VolumeI:AlphabeticalListing/
2011 VolumeII:Appendices,References
ISBN:978-3-527-32118-6 2009
Vol.46 ISBN:978-3-527-31852-0
Vol.41
Ghosh, Arun K.(Ed.)
Aspartic Acid Proteases as van deWaterbeemd, Han/Testa,
Bernard(Eds.)
Therapeutic Targets
Drug Bioavailability
2010
EstimationofSolubility,Permeability,
ISBN:978-3-527-31811-7
AbsorptionandBioavailability
Vol.45
Second,CompletelyRevisedEdition
Ecker, GerhardF. /Chiba,Peter (Eds.)
2008
Transporters as Drug Carriers
ISBN:978-3-527-32051-6
Structure,Function,Substrates Vol.40
2009 Ottow,Eckhard/Weinmann,Hilmar(Eds.)
ISBN:978-3-527-31661-8
Nuclear Receptors
Vol.44
as Drug Targets
Faller,Bernhard /Urban,Laszlo(Eds.)
2008
Hit and Lead Profiling
ISBN:978-3-527-31872-8
IdentificationandOptimization Vol.39
ofDrug-likeMolecules
Vaz,Roy J./Klabunde, Thomas(Eds.)
2009
Antitargets
ISBN:978-3-527-32331-9
Vol.43 PredictionandPrevention
ofDrugSideEffects
Sippl, Wolfgang/Jung,Manfred (Eds.)
2008
Epigenetic Targets in Drug
ISBN:978-3-527-31821-6
Discovery Vol.38
2009 Mannhold,Raimund (Ed.)
ISBN:978-3-527-32355-5
Molecular Drug Properties
Vol.42
MeasurementandPrediction
2007
ISBN:978-3-527-31755-4
Vol.37
Edited by
Jarkko Rautio
Prodrugs and Targeted Delivery
Towards Better ADME Properties
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Prodrugsarebioreversiblederivativesofdrugmole- PrintingandBinding betz-druckGmbH,Darmstadt
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(LaskowskianatomytakenwithcourtesyoftheU.S. ISBN:978-3-527-32603-7
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V
Contents
List of Contributors XVII
Preface XXI
A Personal Foreword XXIII
PartOne ProdrugDesignandIntellectualProperty 1
1 ProdrugStrategiesinDrugDesign 3
JarkkoRautio
1.1 ProdrugConcept 3
1.2 BasicsofProdrugDesign 4
1.3 RationaleforProdrugDesign 5
1.3.1 OvercomingFormulationandAdministrationProblems 6
1.3.2 OvercomingAbsorptionBarriers 8
1.3.3 OvercomingDistributionProblems 9
1.3.4 OvercomingMetabolismandExcretionProblems 10
1.3.5 OvercomingToxicityProblems 10
1.3.6 LifeCycleManagement 13
1.4 HistoryofProdrugDesign 14
1.5 RecentlyMarketedProdrugs 17
1.5.1 ProdrugPrevalence 17
1.5.2 RecentProdrugApprovals 17
1.6 ConcludingRemarks 25
References 26
2 TheMolecularDesignofProdrugsbyFunctionalGroup 31
VictorR.Guarino
2.1 Introduction 31
2.2 TheProdrugConceptandBasicsofDesign 32
2.3 CommonFunctionalGroupApproachesinProdrugDesign 34
ProdrugsandTargetedDelivery:TowardsBetterADMEProperties.EditedbyJarkkoRautio
Copyright(cid:1)2011WILEY-VCHVerlagGmbH&Co.KGaA,Weinheim
ISBN:978-3-527-32603-7
VI Contents
2.3.1 AliphaticandAromaticAlcohols 34
2.3.1.1 PhosphateMonoesters 35
2.3.1.2 SimpleAcylEsters 37
2.3.1.3 AminoAcidEsters 38
2.3.1.4 OtherEster-BasedApproaches 39
2.3.2 CarboxylicAcids 40
2.3.2.1 AlkylEsters 41
2.3.2.2 AminoalkylEsters 42
2.3.2.3 SpacerGroupstoAlleviateStericHindrance 42
2.3.3 Imides,Amides,andOtherNHAcids 43
2.3.3.1 Imide-TypeNHAcids 44
2.3.3.2 Amide-TypeNHAcids 44
2.3.3.3 SulfonamideNHAcids 48
2.3.4 Phosphates,Phosphonates,andPhosphinates 49
2.3.4.1 SimpleAlkylandArylEsters 49
2.3.4.2 AcyloxyalkylandAlkoxycarbonyloxyalkylEsters 50
2.3.4.3 ArylPhospho(n/r)amidatesandPhospho(n/r)diamides 51
2.3.4.4 HepDirectTechnology 53
2.3.5 AminesandBenzamidines 53
2.3.5.1 N-AcyloxyalkoxycarbonylProdrugs 54
2.3.5.2 N-MannichBases 55
2.3.5.3 N-AcyloxyalkylandN-PhosphoryloxyalkylProdrugsofTertiary
Amines 55
2.3.5.4 N-HydroxyandOtherModificationsforBenzamidines 56
2.4 Conclusions 56
References 57
3 IntellectualPropertyPrimeronPharmaceuticalPatentswith
aSpecialEmphasisonProdrugsandMetabolites 61
EyalH.Barash
3.1 Introduction 61
3.2 PatentsandFDAApprovalProcess 61
3.3 ObtainingaPatent 65
3.3.1 Utility 66
3.3.2 Novelty 67
3.3.3 Nonobviousness 71
3.4 Conclusion 78
PartTwo ProdrugsAddressingADMETIssues 79
4 IncreasingLipophilicityforOralDrugDelivery 81
MajidY.Moridani
4.1 Introduction 81
4.2 pK ,DegreeofIonization,PartitionCoefficient,andDistribution
a
Coefficient 81
Contents VII
4.3 ProdrugStrategiestoEnhanceLipidSolubility 85
4.4 ProdrugExamplesforAntibiotics 87
4.4.1 Bacampicillin 87
4.4.2 Carindacillin 88
4.4.3 CefditorenPivoxil 89
4.4.4 CefuroximeAxetil 90
4.4.5 CefpodoximeProxetil 91
4.5 AntiviralRelatedProdrugs 92
4.5.1 Oseltamivir 92
4.5.2 Famciclovir 92
4.5.3 AdefovirDipivoxil 93
4.5.4 TenofovirDisoproxil 94
4.6 CardiovascularRelatedProdrugs 95
4.6.1 Enalapril 95
4.6.2 Fosinopril 96
4.6.3 OlmesartanMedoxomil 97
4.7 LipophilicProdrugsofBenzamidineDrugs 98
4.7.1 Ximelagatran 98
4.7.2 DabigatranEtexilate 99
4.8 MiscellaneousExamples 100
4.8.1 Capecitabine 100
4.8.2 MycophenolateMofetil 101
4.8.3 Misoprostol 102
4.8.4 AdditionalExamples 102
4.9 SummaryandConclusion 104
References 106
5 ModulatingSolubilityThroughProdrugsforOral
andIVDrugDelivery 111
VictorR.Guarino
5.1 Introduction 111
5.2 BasicsofSolubilityandOral/IVDrugDelivery 112
5.2.1 SomeBasicFundamentalsofSolubility 112
5.2.2 SomeGeneralCommentsonIVDrugDelivery 114
5.2.3 SomeGeneralCommentsonOralDrugDelivery 116
5.3 ProdrugApplicationsforEnhancedAqueousSolubility 117
5.3.1 ProdrugConcept 117
5.3.2 ExamplesofProdrugstoEnhanceAqueousSolubility
forIVAdministration 118
5.3.2.1 Fosphenytoin 118
5.3.2.2 Fospropofol 119
5.3.2.3 Parecoxib 120
5.3.2.4 Irinotecan 120
5.3.3 ProdrugstoEnhanceAqueousSolubilityforOralAdministration 121
5.3.3.1 Fosamprenavir 121
VIII Contents
5.3.3.2 Valganciclovir 122
5.4 ChallengeswithSolubilizingProdrugsofInsolubleDrugs 123
5.4.1 ChallengeswithSolubilizingProdrugStrategiesfor
IVAdministration 123
5.4.2 ChallengeswithSolubilizingProdrugStrategiesfor
OralAdministration 124
5.5 AdditionalApplicationsofProdrugsforModulatingSolubility 125
5.5.1 AlleviatingpH-DependentOralBioavailabilityofWeakly
BasicDrugs 126
5.5.2 AligningpH-SolubilityandpH-StabilityRelationships
forIVProducts 126
5.5.3 ModulatingSolubilityinNegativeDirection 127
5.6 ParallelExplorationofAnaloguesandProdrugsinDrug
Discovery(Commentary) 128
5.7 Conclusions 129
References 129
6 ProdrugsDesignedtoTargetTransportersforOralDrugDelivery 133
MarkS.WarrenandJarkkoRautio
6.1 Introduction 133
6.2 Serendipity:AnActivelyTransportedProdrug 133
6.3 RequirementsforActivelyTransportedProdrugs 135
6.4 PeptideTransporters:PEPT1andPEPT2 135
6.5 MonocarboxylateTransporters 140
6.6 BileAcidTransporters 143
6.7 Conclusions 147
References 147
7 TopicalandTransdermalDeliveryUsingProdrugs:
MechanismofEnhancement 153
KennethSloan,ScottC.Wasdo,andSusrutaMajumdar
7.1 Introduction 153
7.2 ArrangementofWaterintheStratumCorneum 155
7.3 ANewModelforDiffusionThroughtheStratumCorneum:
TheBiphasicSolubilityModel 156
7.4 EquationsforQuantifyingEffectsofSolubilityonDiffusion
ThroughtheStratumCorneum 158
7.4.1 TheRoberts–SloanEquationWhentheVehicleisWater 159
7.4.2 TheRoberts–SloanEquationWhentheVehicleisaLipid 160
7.4.3 TheSeries/ParallelEquationWhentheVehicleisaLipid 161
7.5 DesignofProdrugsforTopicalandTransdermalDelivery
BasedontheBiphasicSolubilityModel 162
7.5.1 5-FluorouracilProdrugs 164
7.5.1.1 N-Acyl5-FUProdrugs 165
7.5.1.2 N-SoftAlkyl5-FUProdrugs 166
Contents IX
7.5.2 Acetaminophen(APAP)Prodrugs 167
7.5.2.1 O-AcylAPAPProdrugs 168
7.5.2.2 O-SoftAlkylAPAPProdrugs 170
7.5.3 S-SoftAlkylProdrugsof6-Mercaptopurine 170
7.5.3.1 EffectofVehiclesonTopicalandTransdermalDelivery 171
7.6 ComparisonofHumanandMouseSkinExperiments 172
7.7 Summary 174
References 175
8 OcularDeliveryUsingProdrugs 181
DeepKwatra,RaviVaishya,RipalGaudana,JwalaJwala,
andAshimK.Mitra
8.1 Introduction 181
8.2 CriteriaforanIdealOphthalmicProdrug 181
8.3 AnatomyandPhysiologyoftheEye 182
8.3.1 AnteriorChamber 183
8.3.2 PosteriorChamber 183
8.4 BarrierstoOcularDrugDelivery 184
8.4.1 TearFilm 184
8.4.2 CornealEpithelium 184
8.4.3 AqueousHumorandBAB 184
8.4.4 Conjunctiva 184
8.4.5 Blood–RetinalBarrier 185
8.5 InfluxandEffluxTransportersontheEye 185
8.6 Transporter-TargetedProdrugApproach 186
8.6.1 Acyclovir 186
8.6.2 Ganciclovir 188
8.6.3 Quinidine 188
8.7 DrugDispositioninOcularDelivery 189
8.8 EffectofPhysiochemicalFactorsonDrugDispositioninEye 190
8.9 ProdrugStrategytoImproveOcularBioavailability
(Nontransporter-TargetedApproach) 192
8.9.1 Epinephrine 192
8.9.2 Phenylephrine 192
8.9.3 Pilocarpine 193
8.9.4 Timolol 195
8.9.5 ProstaglandinF2a 197
8.10 RecentPatentsandMarketedOcularProdrugs 198
8.11 NovelFormulationApproachesforSustainedDeliveryofProdrugs 201
8.12 Conclusion 201
References 202
9 ReducingPresystemicDrugMetabolism 207
MajidY.Moridani
9.1 Introduction 207
X Contents
9.2 PresystemicMetabolicBarriers 209
9.2.1 Esterases 209
9.2.2 CytochromeP450Enzymes 212
9.2.3 PhaseIIDrugMetabolizingEnzymes 214
9.2.4 Peptidases 215
9.2.5 OtherOxidativeMetabolizingEnzymes 216
9.3 ProdrugApproachestoReducePresystemicDrugMetabolism 217
9.4 TargetingColon 220
9.5 TargetingLymphaticRoute 221
9.6 Conclusion 225
References 226
10 Enzyme-ActivatedProdrugStrategiesforSite-Selective
DrugDelivery 231
KristaLaineandKristiinaHuttunen
10.1 Introduction 231
10.2 GeneralRequirementsforEnzyme-ActivatedTargeted
ProdrugStrategy 232
10.3 ExamplesofTargetedProdrugStrategies 232
10.3.1 Tumor-SelectiveProdrugs 232
10.3.1.1 ProdrugsActivatedbyHypoxia-AssociatedReductiveEnzymes 233
10.3.1.2 ProdrugsActivatedbyGlutathioneS-Transferase 236
10.3.1.3 ProdrugsActivatedbyThymidinePhosphorylase 237
10.3.2 Organ-SelectiveProdrugs 239
10.3.2.1 Liver-TargetedProdrugs 239
10.3.2.2 Kidney-TargetedProdrugs 242
10.3.2.3 Colon-TargetedProdrugs 243
10.3.3 Virus-SelectiveProdrugs 244
10.4 Summary 245
References 246
11 ProdrugApproachesforCentralNervousSystemDelivery 253
QuentinR.SmithandPaulR.Lockman
11.1 Blood–BrainBarrierinCNSDrugDevelopment 253
11.2 ProdrugStrategies 255
11.3 ProdrugStrategiesBasedUponBBBNutrientTransporters 257
11.4 ProdrugStrategiesBasedUponBBBReceptors 263
11.5 CNSProdrugSummary 264
References 266
12 DirectedEnzymeProdrugTherapies 271
DanNiculescu-Duvaz,GabrielNegoita-Giras,IonNiculescu-Duvaz,
DouglasHedley,andCarolineJ.Springer
12.1 Introduction 271
12.2 TheoreticalBackgroundofDEPT 271