Retrometabolic Drug Design and Targeting

440 Pages·2012·27.836 MB·English

by  Nicholas Bodor, Peter Buchwald

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RETROMETABOLIC DRUG DESIGN
AND TARGETING
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RETROMETABOLIC DRUG DESIGN
AND TARGETING
Nicholas Bodor
CenterforDrugDiscovery
UniversityofFlorida
Gainesville,Florida
Peter Buchwald
DiabetesResearchInstituteandMolecular
andCellularPharmacology
MillerSchoolofMedicine
UniversityofMiami
Miami,Florida
AJOHNWILEY&SONS,INC.,PUBLICATION
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LibraryofCongressCataloging-in-Publication
Bodor,Nicholas.
Retrometabolicdrugdesignandtargeting/NicholasBodor,PeterBuchwald.
p.;cm.
Includesbibliographicalreferencesandindex.
ISBN978-0-470-94945-0(cloth)
I.Buchwald,Peter.II.Title.
[DNLM:1.DrugDesign. 2.DrugDeliverySystems. 3.DrugEvaluation,Preclinical.
4.PharmaceuticalPreparations–metabolism.QV745]
615.1(cid:2)9–dc23
2012020183
PrintedintheUnitedStatesofAmerica
10 9 8 7 6 5 4 3 2 1
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CONTENTS
Preface ix
1 Introduction 1
1.1 NewDrugsandMedicalProgress 1
1.2 TheChallengeofNewDrugDiscovery 5
References 7
2 MechanismofDrugAction:BasicConcepts 9
2.1 PharmacodynamicPhase:Drug–ReceptorInteractions 10
2.1.1 TheReceptorConceptandReceptorTypes 10
2.1.2 Ligand–ReceptorBinding 12
2.1.3 ReceptorOccupancyandActivation 16
2.2 PharmacokineticPhase:ADME 20
2.2.1 DrugAbsorptionandDistribution 20
2.2.2 DrugMetabolismandExcretion 22
2.2.3 BasicPharmacokineticConcepts 26
2.3 StructuralRequirements:KeepingIt“Drug-Like” 29
2.3.1 TheDrug-LikeChemicalSpace 29
2.3.2 OralDrugs:TheChallengeofBioavailability 31
References 33
3 TheDrugDiscoveryandDevelopmentProcess 39
3.1 DiscoveryResearch 39
3.1.1 Prediscovery 39
3.1.2 TargetIdentification 41
3.1.3 TargetValidation 42
3.1.4 Target-to-HitandHit-to-LeadDevelopment 42
3.1.5 EarlyDistributionandSafetyTests 46
3.1.6 LeadOptimization 48
3.2 PreclinicalDevelopment 49
3.2.1 PreclinicalTesting 49
3.2.2 InvestigationalNewDrugApplicationandSafety 50
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vi CONTENTS
3.3 ClinicalDevelopment 51
3.3.1 PhaseIClinicalTrials 51
3.3.2 PhaseIIClinicalTrials 51
3.3.3 PhaseIIIClinicalTrials 52
3.4 RegulatoryApprovalandPostMarketingDevelopment 53
3.4.1 NewDrugApplicationandRegulatoryApproval 53
3.4.2 Manufacturing 54
3.4.3 PostapprovalStudiesandPhaseIVTrials 54
3.4.4 PatentExpirationandGenericApproval 54
3.5 ProblemswiththeCurrentParadigm 56
3.5.1 DecreasingR&DEfficiency 56
3.5.2 TheDrugDiscoveryProcess:ImprovementsNeeded 62
References 64
4 RetrometabolicDrugDesign 71
4.1 DesignPrinciples 71
4.2 Terminology 72
4.2.1 SoftDrugvs.HardDrug 72
4.2.2 SoftDrugvs.Prodrug 73
4.2.3 ChemicalDeliverySystemvs.Prodrug 73
References 74
5 SoftDrugs 77
5.1 EnzymaticHydrolysis 78
5.1.1 Esterases 79
5.1.2 InterspeciesVariability 81
5.1.3 InterorganandInterindividualVariability 82
5.1.4 Mechanism:CatalyticTriadandOxyanionHole 83
5.1.5 Kinetics 84
5.1.6 Stereoselectivity 85
5.1.7 ActivationEnergyandTemperatureDependence 85
5.1.8 Structure–MetabolismRelationships 86
5.1.9 Rate-InfluencingRoleoftheAlcoholorAcylSide
Chain 92
5.2 SoftDrugApproaches 93
5.3 InactiveMetabolite–BasedSoftDrugs 96
5.3.1 SoftBeta-Blockers 97
5.3.2 SoftOpioidAnalgetics:Remifentanil 106
5.3.3 SoftCorticosteroids 109
5.3.4 SoftCalcitriol(1(cid:2),25–DihydroxyvitaminD )
3
Analogs 137
5.3.5 SoftEstrogens 138
5.3.6 Soft(cid:3) -Agonists 140
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CONTENTS vii
5.3.7 SoftPsychostimulants 142
5.3.8 SoftInsecticidesandPesticides 144
5.3.9 SoftAnticholinergics:InactiveMetabolite–Based
Approach 147
5.4 SoftAnalogs 151
5.4.1 SoftAnticholinergics:SoftQuaternaryAnalogs 152
5.4.2 SoftAntimicrobials 154
5.4.3 SoftAntiarrhythmicAgents 156
5.4.4 SoftSerotoninReceptorAgonists:Naronapride 160
5.4.5 SoftAnticoagulants(VitaminKAntagonists):
Tecarfarin 162
5.4.6 SoftAngiotensinConvertingEnzymeInhibitors 164
5.4.7 SoftDihydrofolateReductaseInhibitors 165
5.4.8 SoftCalcineurinInhibitors(Soft
Immunosuppressants) 166
5.4.9 SoftCytokineModulators 169
5.4.10 SoftPhosphodiesterase4Inhibitors 171
5.4.11 SoftMatrixMetalloproteinaseInhibitors 173
5.4.12 SoftCannabinoids 173
5.4.13 SoftBenzodiazepineAnalogs:Remimazolamand
Analogs 175
5.4.14 SoftAnesthetics 178
5.4.15 SoftCa2+ChannelBlockers 182
5.5 ActiveMetabolite–BasedSoftDrugs 184
5.6 ActivatedSoftDrugs 186
5.7 Pro-SoftDrugs 188
5.7.1 Pro-SoftDrugsofNaturalSoftDrugs:Hormone
Prodrugs 188
5.7.2 Pro-SoftDrugsofPeptidylBoronicAcidDerivatives 188
5.8 Computer-AidedDesign 191
5.8.1 Computer-AidedSoftDrugDesign 192
5.8.2 PredictingMolecularProperties 194
5.8.3 MolecularSize 194
5.8.4 Lipophilicity:Octanol/WaterPartitionCoefficient 196
5.8.5 WaterSolubility 205
5.8.6 StructureGeneration 206
5.8.7 CandidateRanking 206
5.8.8 HydrolyticLability 208
5.8.9 Illustrations 209
5.9 SoftDrugs:Summary 215
References 215
6 ChemicalDeliverySystems 259
6.1 EnzymaticPhysicochemical-Based(Brain-Targeting)CDSs 260
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6.1.1 TheChallengeofBrainTargeting 260
6.1.2 TheBlood–BrainBarrier 260
6.1.3 Brain-TargetingDrugDeliveryApproaches 263
6.1.4 Brain-TargetingCDSs:Details 274
6.1.5 QuantifyingDelivery 282
6.1.6 GenesisoftheCDSConcept:Pro-2-PAM 284
6.1.7 Berberine 288
6.1.8 DopamineCDS 290
6.1.9 Zidovudine(AZT)CDS 292
6.1.10 OtherAntiviralandAntiretroviralCDSs 294
6.1.11 AnticancerCDSs 299
6.1.12 OtherBrain-TargetingCDSs 302
6.1.13 EstradiolCDS 307
6.1.14 CyclodextrinComplexes 328
6.1.15 MolecularPackaging 331
6.2 Site-SpecificEnzyme-Activated(Eye-Targeting)CDSs 346
6.2.1 TheChallengeofOcularTargeting 346
6.2.2 PotentialTherapeuticApplications:Glaucoma 347
6.2.3 Eye-TargetingCDSs:DesignPrinciples 348
6.2.4 OximeandMethoximeAnalogsofBeta-Blockers 350
6.3 Receptor-BasedTransientAnchor-TypeCDSs 357
References 358
Conclusions 395
Index 397