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
Autorentext
Li Di is an associate research fellow in the Pharmacokinetics, Dynamics, and Drug Metabolism Department at Pfizer Global Research and Development and has extensive experience in the pharmaceutical industry. She has over 100 publications, presented over 70 invited lectures, and teaches an American Chemical Society short course on drug-like properties.
Edward Kerns worked in pharmaceutical research and development for over 30 years, was associate director at Wyeth and Bristol-Myers Squibb, then was at the NIH-National Center for Advancing Translational Sciences. He published over 90 journal papers or book chapters and 3 books, and teaches an American Chemical Society short course on drug-like properties.
Klappentext
Central nervous system (CNS) drugs are a leading pharmaceutical area, since many CNS diseases remain untreated or without optimum drugs. Unfortunately, the blood-brain barrier (BBB) restricts access of drug molecules circulating in the blood stream to penetrate into the brain cells and that is where this important book steps in.
With practical and proven solutions for CNS drug discovery efforts, this book educates drug researchers about the BBB so they can affect important improvements in one of the most significant and most challenging areas of drug discovery.
The chapters are written by world-class scientists actively engaged in CNS research from both academia and industry, applying this to more quickly discover and develop better drugs. Among the topics they review are state-of-the-art in silico, in vitro, and in vivo tools for assessing the BBB and advanced delivery technologies. Coverage includes fundamental knowledge about the BBB, implications of these restrictions on free drug exposure at the target in brain, pharmacokinetics (PK) and pharmacodynamics (PD) relationships (PK/PD), physiologically-based pharmacokinetic (PBPK) brain models, medicinal chemistry design principles, and case studies from successful CNS drug discovery. These case studies examine how the integration of data and design strategies advanced successful new drugs to market.
A unique and valuable reference resource for practicing medicinal chemists, this book:
• Focuses on practical solutions of brain exposure problems faced by drug researchers
• Helps readers understand, control and measure the exposure of the drug candidates to the CNS
• 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
• Discusses case studies of successful CNS and non-CNS drugs, lessons learned and paths to the market
Zusammenfassung
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
Inhalt
Contributors ix
Preface xiii
1 Introduction and Overview 1
li di and Edward H. Kerns
Part 1 Pharmacokinetics of Brain Exposure 5
2 Pharmacokinetics of CNS Penetration 7
Andreas Reichel
3 Free Drug Hypothesis for CNS Drug Candidates 42
Xingrong Liu and Cuiping Chen
4 Species Differences and Impact of Disease State on BBB 66
Jean-Marie Nicolas
Part 2 Mechanisms of Drugs Across the BloodBrain Barrier 95
5 Passive Diffusion Permeability of the BBBExamples and SAR 97
Scott Summerfield, Phil Jeffrey, Jasminder Sahi, and Liangfu Chen
6 Establishment of P-Glycoprotein StructureTransport Relationships to Optimize CNS Exposure in Drug Discovery 113
Jerome H. Hochman, Sookhee N. Ha, and Robert P. Sheridan
7 Uptake Transport at the BBBExamples and SAR 125
Ziqiang Cheng and Qian Liu
8 Transport of Protein and Antibody Therapeutics across the BloodBrain Barrier 146
William M. Pardridge
Part 3 Predicting and Measuring Brain Exposure of Drugs 167
9 In Silico Tools for Predicting Brain Exposure of Drugs 169
Hongming Chen, Susanne Winiwarter, and Ola Engkvist
10 In Vitro Assays for Assessing BBB Permeability: Artificial Membrane and Cell Culture Models 188
Alex Avdeef, Mária A. Deli, and Winfried Neuhaus
11 Human-Based In Vitro Brain Endothelial Cell Models 238
Hannah K. Wilson and Eric V. Shusta
12 Methods for Assessing Brain Binding 274
li di and Cheng Chang
13 In Vivo Studies of Brain Exposure in Drug Discovery 284
Edward H. Kerns
14 PBPK Modeling Approach for Predictions of Human CNS Drug Brain Distribution 296
Elizabeth C.M. de Lange
15 PK/PD Modeling of CNS Drug Candidates 324
Johan Gabrielsson, Stephan Hjorth, and Lambertus A. Peletier
16 Microdialysis to Assess Free Drug Concentration in Brain 351
William Kielbasa and Robert E. Stratford, Jr.
17 Imaging Techniques for Central Nervous System (CNS) Drug Discovery 365
Lei Zhang and Anabella Villalobos
Part 4 Modulating Brain Penetration of Leads During Drug Discovery 385
18 Designing CNS Drugs for Optimal Brain Exposure 387
Zoran Rankovic
19 Case Studies of CNS Drug OptimizationMedicinal Chemistry and CNS Biology Perspectives 425
Kevin J. Hodgetts
20 Designing Peripheral Drugs for Minimal Brain Exposure 446
Peter Bungay, Sharan Bagal, and Andy Pike
21 Case Studies of Non-CNS Drugs to Minimize Brain PenetrationNonsedative Antihistamines 463
Andrew Crowe
Part 5 Case Studies in CNS Drug Discovery 483
22 Case Study 1: The Discovery and Development of Perampanel 485
Antonio La…