Prodrugs and Targeted Delivery

This topical reference and handbook addresses the chemistry, pharmacology, toxicology and the patentability of prodrugs, perfectly mirroring the integrated approach prevalent in today's drug design. It summarizes current experiences and strategies for the rational design of prodrugs, beginning at the early stages of the development process, as well as discussing organ- and site-selective prodrugs. Every company employing medicinal chemists will be interested in this practice-oriented overview of a key strategy in modern drug discovery and development.

This topical reference and handbook addresses the chemistry, pharmacology, toxicology and the patentability of prodrugs, perfectly mirroring the integrated approach prevalent in today's drug design. It summarizes current experiences and strategies for the rational design of prodrugs, beginning at the early stages of the development process, as well as discussing organ- and site-selective prodrugs.Every company employing medicinal chemists will be interested in this practice-oriented overview of a key strategy in modern drug discovery and development.

PrefacePART ONE: Prodrug Design and Intellectual PropertyPRODRUG STRATEGIES IN DRUG DESIGNProdrug ConceptBasics of Prodrug DesignRationale for Prodrug DesignHistory of Prodrug DesignRecently Marketed ProdrugsConcluding RemarksTHE MOLECULAR DESIGN OF PRODRUGS BY FUNCTIONAL GROUPIntroductionThe Prodrug Concept and Basics of DesignCommon Functional Group Approaches in Prodrug DesignConclusionsINTELLECTUAL PROPERTY PRIMER ON PHRAMACEUTICAL PATENTS WITH A SPECIAL EMPHASIS ON PRODRUGS AND METABOLITESIntroductionPatents and FDA Approval ProcessObtaining a PatentConclusionPART TWO: Prodrugs Addressing ADMET IssuesINCREADING LIPOPHILICITY FOR ORAL DRUG DELIVERYIntroductionpKa, Degree of Ionization, Partition Coefficient, and Distribution CoefficientProdrug Strategies to Enhance Lipid SolubilityProdrug Examples for AntibioticsAntiviral Related ProdrugsCardiovascular Related ProdrugsLipophilic Prodrugs of Benzamidine DrugsMiscellaneous ExamplesSummary and ConclusionMODULATING SOLUBILITY THROUGH PRODRUGS FOR ORAL AND IV DRUG DELIVERYIntroductionBasics of Solubility and Oral/IV Drug DeliveryProdrug Applications for Enhanced Aqueous SolubilityChallenges with Solubilizing Prodrugs of Insoluble DrugsAdditional Applications of Prodrugs for Modulating SolubilityParallel Exploration of Analogues and Prodrugs in Drug Discovery (Commentary)ConclusionsPRODRUGS DESIGNED TO TARGET TRANSPORTERS FOR ORAL DRUG DELIVERYIntroductionSerendipity: An Actively Transported ProdrugRequirements for Actively Transported ProdrugsPeptide Transporters: PEPT1 and PEPT2Monocarboxylate TransportersBile Acid TransportersConclusionsTOPICAL AND TRANSDERMAL DELIVERY USING PRODRUGS: MECHANISM OF ENHANCEMENTIntroductionArrangement of Water in the Stratum CorneumA New Model for Diffusion Through the Stratum Corneum: The Biphasic Solubility ModelEquations for Quantifying Effects of Solubility on Diffusion Through the Stratum CorneumDesign of Prodrugs for Topical and Transdermal Delivery Based on the Biphasic Solubility ModelComparison of Human and Mouse Skin ExperimentsSummaryOCULAR DELIVERY USING PRODRUGSIntroductionCriteria for an Ideal Ophthalmic ProdrugAnatomy and Physiology of the EyeBarriers to Ocular Drug DeliveryInflux and Efflux Transporters on the EyeTransporter-Targeted Prodrug ApproachDrug Disposition in Ocular DeliveryEffect of Physiochemical Factors on Drug Disposition in EyeProdrug Strategy to Improve Ocular Bioavailability (Nontransporter-Targeted Approach)Recent Patents and Marketed Ocular ProdrugsNovel Formulation Approaches for Sustained Delivery of ProdrugsConclusionREDUCING PRESYSTEMIC DRUG METABOLISMIntroductionPresystemic Metabolic BarriersProdrug Approaches to Reduce Presystemic Drug MetabolismTargeting ColonTargeting Lymphatic RouteConclusionENZYME-ACTIVATED PRODRUG STRATEGIES FOR SITE-SELECTIVE DRUG DELIVERYIntroductionGeneral Requirements for Enzyme-Activated Targeted Prodrug StrategyExamples of Targeted Prodrug StrategiesSummaryPRODRUG APPROACHES FOR CENTRAL NERVOUS SYSTEM DELIVERYBlood-Brain Barrier in CNS Drug DevelopmentProdrug StrategiesProdrug Strategies Based Upon BBB Nutrient TransportersProdrug Strategies Based Upon BBB ReceptorsCNS Prodrug SummaryDIRECTED ENZYME PRODRUG THERAPIESIntroductionTheoretical Background of DEPTComparison of ADEPT and GDEPTEnzymes in ADEPT and GDEPTDesign of ProdrugsStrategies Used for the Improvement of DEPT SystemsBiological Data for ADEPT and GDEPTConclusionsPART THREE: Codrugs and Soft DrugsIMPROVING THE USE OF DRUG COMBINATIONS THROUGH THE CODRUG APPROACHCodrugs and Codrug StrategyIdeal Codrug CharacteristicsExamples of Marketed CodrugsTopical Codrug Therapy for the Treatment of Ophthalmic DiseasesCodrugs for Transdermal DeliveryCodrugs of L-DOPA for the Treatment of Parkinson's DiseaseAnalgesic Codrugs Containing Nonsteroidal Anti-Inflammatory AgentsAnalgesic Codrugs of Opioids and Cannabinoi