Blood-Brain Barrier in Drug Discovery E-Book

• Herausgeber: John Wiley & Sons
• Kategorie: Wissenschaft und neue Technologien
• Sprache: Englisch

Seitenzahl: 1214

Veröffentlichungsjahr: 2014

Beschreibung

Focused on central nervous system (CNS) drug discovery efforts, this book educates drug researchers about the blood-brain barrier (BBB) so they can affect important improvements in one of the most significant - and most challenging - areas of drug discovery. * Written by world experts to provide practical solutions to increase brain penetration or minimize CNS side-effects * Reviews state-of-the-art in silico, in vitro, and in vivo tools to assess brain penetration and advanced CNS drug delivery strategies * Covers BBB physiology, medicinal chemistry design principles, free drug hypothesis for the BBB, and transport mechanisms including passive diffusion, uptake/efflux transporters, and receptor-mediated processes * Highlights the advances in modelling BBB pharmacokinetics and dynamics relationships (PK/PD) and physiologically-based pharmacokinetics (PBPK) * Discusses case studies of successful CNS and non-CNS drugs, lessons learned and paths to the market

Leseprobe

CONTENTS

Cover

Title page

Copyright page

Contributors

Preface

1 Introduction and Overview

Restricted Brain Exposure Reduces CNS Drug Efficacy

Permitted CNS Access Increases Side Effects of Peripheral Drugs

A New Generation of CNS Exposure Tools

Case Studies of Drug Development Successes

Conclusion

Part 1: Pharmacokinetics of Brain Exposure

2 Pharmacokinetics of CNS Penetration

Introduction

CNS Penetration

NeuroPK

Strategies to Increase/Avoid CNS Penetration/Exposure to Targets within the CNS

Translating NeuroPK from Animals to Humans

Summary and Outlook

References

3 Free Drug Hypothesis for CNS Drug Candidates

Introduction

Use of Brain Homogenate and Brain Slice Methods to Determine Unbound Brain Concentration

In vivo

Pharmacokinetic/Pharmacodynamic Observations to Support Free Drug Hypothesis for CNS Drugs

Strategy to Increase Unbound Brain Concentration in CNS Drug Design

Reduction of Brain Tissue Binding Cannot Increase Unbound Brain Concentration

K

p

Is a Misleading Parameter for the Assessment of Brain Penetration

Summary

References

4 Species Differences and Impact of Disease State on BBB

The Need for a Better Understanding of CNS Drug Disposition

The Key Parameters Describing Drug Delivery into the Brain

Species Differences in Drug Delivery into the Brain

BBB Properties in Disease States

Conclusions

References

Part 2: Mechanisms of Drugs Across the Blood–Brain Barrier

5 Passive Diffusion Permeability of the BBB—Examples and SAR

Introduction

Points to Consider for

In Vitro–In Vivo

Correlations

In Vitro

Models and Measurements

Cell-Based Permeability Assays

In Vivo

Models and Measurements

In Silico

Models

Summary

References

6 Establishment of P-Glycoprotein Structure–Transport Relationships to Optimize CNS Exposure in Drug Discovery

Transport Models Surrogated for the Blood–Brain Barrier

P-gp Transport Mechanisms and Drug Properties

Establishment of SAR in Discovery Programs

Conclusions

References

7 Uptake Transport at the BBB—Examples and SAR

Introduction

OATP1A2

OATP2B1

LAT

ENT1

MCT1

Discussion and Future Perspective

References

8 Transport of Protein and Antibody Therapeutics across the Blood–Brain Barrier

Biotechnology and the Brain: Historical Perspective

Blood–Brain Barrier Molecular Trojan Horse Technology

Reengineering Recombinant Protein Therapeutics as IgG Fusion Proteins

IgG Fusion Proteins for Targeted BBB Delivery

Pharmacologic Effects in Mouse Models of Neural Disease

Reengineering Therapeutic Antibodies as BBB-Penetrating Bispecific Antibodies

Reengineering an Anti-Amyloid Antibody as a BBB-Penetrating Bispecific Antibody

Pharmacologic Effects in a Mouse Model of Alzheimer’s Disease

Safety Pharmacology of Molecular Trojan Horse Fusion Proteins in Mice and Primates

Antidrug Antibody Response to IgG Fusion Proteins

Summary

References

Part 3: Predicting and Measuring Brain Exposure of Drugs

9 In Silico Tools for Predicting Brain Exposure of Drugs

Introduction

Measurements Quantifying Brain Exposure of Drugs

Modeling Strategies for Building BBB Models

In silico Models for Predicting logBB

In Silico Models for Predicting logPS

BBB+/BBB– (CNS+/CNS–) Classification Models

Prediction of Unbound Drug Exposure in the Brain,

K

p,uu,brain

Future Development and Challenges

Conclusions

References

10 In Vitro Assays for Assessing BBB Permeability: Artificial Membrane and Cell Culture Models

Introduction

Artificial Membrane Models

Cell Culture Models

Conclusion and Outlook