Rautio Prodrugs and Targeted Delivery

Towards Better ADME Properties
1. Auflage 2010
ISBN: 978-3-527-63317-3
Verlag: Wiley-VCH
Format: PDF
Kopierschutz: Adobe DRM (»Systemvoraussetzungen)

E-Book, Englisch, Band 47, 496 Seiten, E-Book

Reihe: Methods and Principles in Medicinal Chemistry

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.

Autoren/Hrsg.

Rautio, Jarkko

Weitere Mitwirkende

Mannhold, Raimund

Kubinyi, Hugo

Folkers, Gerd

Inhaltsverzeichnis

Preface

 

PART ONE: Prodrug Design and Intellectual Property

 

PRODRUG STRATEGIES IN DRUG DESIGN

Prodrug Concept

Basics of Prodrug Design

Rationale for Prodrug Design

History of Prodrug Design

Recently Marketed Prodrugs

Concluding Remarks

 

THE MOLECULAR DESIGN OF PRODRUGS BY FUNCTIONAL GROUP

Introduction

The Prodrug Concept and Basics of Design

Common Functional Group Approaches in Prodrug Design

Conclusions

 

INTELLECTUAL PROPERTY PRIMER ON PHRAMACEUTICAL PATENTS WITH A SPECIAL EMPHASIS ON PRODRUGS AND METABOLITES

Introduction

Patents and FDA Approval Process

Obtaining a Patent

Conclusion

 

PART TWO: Prodrugs Addressing ADMET Issues

 

INCREADING LIPOPHILICITY FOR ORAL DRUG DELIVERY

Introduction

pKa, Degree of Ionization, Partition Coefficient, and Distribution Coefficient

Prodrug Strategies to Enhance Lipid Solubility

Prodrug Examples for Antibiotics

Antiviral Related Prodrugs

Cardiovascular Related Prodrugs

Lipophilic Prodrugs of Benzamidine Drugs

Miscellaneous Examples

Summary and Conclusion

 

MODULATING SOLUBILITY THROUGH PRODRUGS FOR ORAL AND IV DRUG DELIVERY

Introduction

Basics of Solubility and Oral/IV Drug Delivery

Prodrug Applications for Enhanced Aqueous Solubility

Challenges with Solubilizing Prodrugs of Insoluble Drugs

Additional Applications of Prodrugs for Modulating Solubility

Parallel Exploration of Analogues and Prodrugs in Drug Discovery (Commentary)

Conclusions

 

PRODRUGS DESIGNED TO TARGET TRANSPORTERS FOR ORAL DRUG DELIVERY

Introduction

Serendipity: An Actively Transported Prodrug

Requirements for Actively Transported Prodrugs

Peptide Transporters: PEPT1 and PEPT2

Monocarboxylate Transporters

Bile Acid Transporters

Conclusions

 

TOPICAL AND TRANSDERMAL DELIVERY USING PRODRUGS: MECHANISM OF ENHANCEMENT

Introduction

Arrangement of Water in the Stratum Corneum

A New Model for Diffusion Through the Stratum Corneum: The Biphasic Solubility Model

Equations for Quantifying Effects of Solubility on Diffusion Through the Stratum Corneum

Design of Prodrugs for Topical and Transdermal Delivery Based on the Biphasic Solubility Model

Comparison of Human and Mouse Skin Experiments

Summary

 

OCULAR DELIVERY USING PRODRUGS

Introduction

Criteria for an Ideal Ophthalmic Prodrug

Anatomy and Physiology of the Eye

Barriers to Ocular Drug Delivery

Influx and Efflux Transporters on the Eye

Transporter-Targeted Prodrug Approach

Drug Disposition in Ocular Delivery

Effect of Physiochemical Factors on Drug Disposition in Eye

Prodrug Strategy to Improve Ocular Bioavailability (Nontransporter-Targeted Approach)

Recent Patents and Marketed Ocular Prodrugs

Novel Formulation Approaches for Sustained Delivery of Prodrugs

Conclusion

 

REDUCING PRESYSTEMIC DRUG METABOLISM

Introduction

Presystemic Metabolic Barriers

Prodrug Approaches to Reduce Presystemic Drug Metabolism

Targeting Colon

Targeting Lymphatic Route

Conclusion

 

ENZYME-ACTIVATED PRODRUG STRATEGIES FOR SITE-SELECTIVE DRUG DELIVERY

Introduction

General Requirements for Enzyme-Activated Targeted Prodrug Strategy

Examples of Targeted Prodrug Strategies

Summary

 

PRODRUG APPROACHES FOR CENTRAL NERVOUS SYSTEM DELIVERY

Blood-Brain Barrier in CNS Drug Development

Prodrug Strategies

Prodrug Strategies Based Upon BBB Nutrient Transporters

Prodrug Strategies Based Upon BBB Receptors

CNS Prodrug Summary

 

DIRECTED ENZYME PRODRUG THERAPIES

Introduction

Theoretical Background of DEPT

Comparison of ADEPT and GDEPT

Enzymes in ADEPT and GDEPT

Design of Prodrugs

Strategies Used for the Improvement of DEPT Systems

Biological Data for ADEPT and GDEPT

Conclusions

 

PART THREE: Codrugs and Soft Drugs

 

IMPROVING THE USE OF DRUG COMBINATIONS THROUGH THE CODRUG APPROACH

Codrugs and Codrug Strategy

Ideal Codrug Characteristics

Examples of Marketed Codrugs

Topical Codrug Therapy for the Treatment of Ophthalmic Diseases

Codrugs for Transdermal Delivery

Codrugs of L-DOPA for the Treatment of Parkinson's Disease

Analgesic Codrugs Containing Nonsteroidal Anti-Inflammatory Agents

Analgesic Codrugs of Opioids and Cannabinoi

Über Autor(innen)

Jarkko Rautio is professor of pharmaceutical chemistry and head of the multidisciplinary Pharmaceutical and Medicinal Chemistry (PMC) research group at the School of Pharmacy, University of Eastern Finland (formerly University of Kuopio), where he received his PhD in pharmaceutical chemistry in 2000. He subsequently carried out his postdoctoral studies at the University of Maryland, Baltimore, USA, and was a visiting scientist at GlaxoSmithKline, North Carolina, while also co-founding the American Association of Pharmaceutical Scientists (AAPS) Prodrug Focus Group in 2005. Professor Rautio's research focuses on chemistry-based methods, especially prodrugs, to overcome the liabilities of drugs.