Blood–Brain Barrier in Drug Discovery. Optimizing Brain Exposure of CNS Drugs and Minimizing Brain Side Effects for Peripheral Drugs

  • ID: 2936011
  • Book
  • 600 Pages
  • John Wiley and Sons Ltd
1 of 4
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
Note: Product cover images may vary from those shown
2 of 4

Contributors ix

Preface xiii

1 Introduction and Overview 1Li Di and Edward H. Kerns

Part 1 Pharmacokinetics of Brain Exposure 5

2 Pharmacokinetics of CNS Penetration 7Andreas Reichel

3 Free Drug Hypothesis for CNS Drug Candidates 42Xingrong Liu and Cuiping Chen

4 Species Differences and Impact of Disease State on BBB—66Jean–Marie Nicolas

Part 2 Mechanisms of Drugs Across the Blood Brain Barrier 95

5 Passive Diffusion Permeability of the BBB Examples and SAR—97Scott Summerfield, Phil Jeffrey, Jasminder Sahi, and Liangfu Chen

6 Establishment of P–Glycoprotein Structure Transport Relationships to Optimize CNS Exposure in Drug Discovery 113Jerome H. Hochman, Sookhee N. Ha, and Robert P. Sheridan

7 Uptake Transport at the BBB Examples and SAR—125Ziqiang Cheng and Qian Liu

8 Transport of Protein and Antibody Therapeutics across the Blood Brain Barrier 146William M. Pardridge

Part 3 Predicting and Measuring Brain Exposure of Drugs 167

9 In Silico Tools for Predicting Brain Exposure of Drugs 169Hongming Chen, Susanne Winiwarter, and Ola Engkvist

10 In Vitro Assays for Assessing BBB Permeability: Artificial Membrane and Cell Culture Models 188Alex Avdeef, Mária A. Deli, and Winfried Neuhaus

11 Human–Based In Vitro Brain Endothelial Cell Models 238Hannah K. Wilson and Eric V. Shusta

12 Methods for Assessing Brain Binding 274Li Di and Cheng Chang

13 In Vivo Studies of Brain Exposure in Drug Discovery 284Edward H. Kerns

14 PBPK Modeling Approach for Predictions of Human CNS Drug Brain Distribution 296Elizabeth C.M. de Lange

15 PK/PD Modeling of CNS Drug Candidates 324Johan Gabrielsson, Stephan Hjorth, and Lambertus A. Peletier

16 Microdialysis to Assess Free Drug Concentration in Brain 351William Kielbasa and Robert E. Stratford, Jr.

17 Imaging Techniques for Central Nervous System (CNS) Drug Discovery 365Lei Zhang and Anabella Villalobos

Part 4 Modulating Brain Penetration of Leads During Drug Discovery 385

18 Designing CNS Drugs for Optimal Brain Exposure 387Zoran Rankovic

19 Case Studies of CNS Drug Optimization Medicinal Chemistry and CNS Biology Perspectives 425Kevin J. Hodgetts

20 Designing Peripheral Drugs for Minimal Brain Exposure 446Peter Bungay, Sharan Bagal, and Andy Pike

21 Case Studies of Non–CNS Drugs to Minimize Brain Penetration Nonsedative Antihistamines 463Andrew Crowe

Part 5 Case Studies in CNS Drug Discovery 483

22 Case Study 1: The Discovery and Development of Perampanel 485Antonio Laurenza, Jim Ferry, Haichen Yang, Shigeki Hibi, Takahisa Hanada, and Andrew Satlin

23 Case Study 2: The Discovery and Development of the Multimodal Acting Antidepressant Vortioxetine 505Christoffer Bundgaard, Alan L. Pehrson, Connie Sánchez, and Benny Bang–Andersen

Part 6 Drug Delivery Techniques to CNS 521

24 Brain Delivery Using Nanotechnology 523Huile Gao and Xinguo Jiang

25 Intranasal Delivery to the Central Nervous System 535Lisbeth Illum

Part 7 Future Prospects in Blood–Brain Barrier


26 Future Perspectives 569N. Joan Abbott

Index 580

Note: Product cover images may vary from those shown
3 of 4


4 of 4

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.

Note: Product cover images may vary from those shown
5 of 4
Note: Product cover images may vary from those shown