Blood-Brain Barrier in Drug Discovery (eBook)

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.

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 onBBB_66
Jean-Marie Nicolas

Part 2 Mechanisms of Drugs Across the Blood-BrainBarrier 95

5 Passive Diffusion Permeability of the BBB--Examples andSAR_97
Scott Summerfield, Phil Jeffrey, Jasminder Sahi, and LiangfuChen

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

7 Uptake Transport at the BBB--Examples and SAR_125
Ziqiang Cheng and Qian Liu

8 Transport of Protein and Antibody Therapeutics across theBlood-Brain Barrier 146
William M. Pardridge

Part 3 Predicting and Measuring Brain Exposure of Drugs167

9 In Silico Tools for Predicting Brain Exposure of Drugs169
Hongming Chen, Susanne Winiwarter, and Ola Engkvist

10 In Vitro Assays for Assessing BBB Permeability: ArtificialMembrane 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 DrugBrain 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 Brain351
William Kielbasa and Robert E. Stratford, Jr.

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

Part 4 Modulating Brain Penetration of Leads During DrugDiscovery 385

18 Designing CNS Drugs for Optimal Brain Exposure 387
Zoran Rankovic

19 Case Studies of CNS Drug Optimization--MedicinalChemistry and CNS Biology Perspectives 425
Kevin J. Hodgetts

20 Designing Peripheral Drugs for Minimal Brain Exposure446
Peter Bungay, Sharan Bagal, and Andy Pike

21 Case Studies of Non-CNS Drugs to Minimize BrainPenetration--Nonsedative Antihistamines 463
Andrew Crowe

Part 5 Case Studies in CNS Drug Discovery 483

22 Case Study 1: The Discovery and Development of Perampanel485
Antonio Laurenza, Jim Ferry, Haichen Yang, Shigeki Hibi,Takahisa Hanada, and Andrew Satlin

23 Case Study 2: The Discovery and Development of the MultimodalActing Antidepressant Vortioxetine 505
Christoffer Bundgaard, Alan L. Pehrson, Connie Sánchez, andBenny Bang-Andersen

Part 6 Drug Delivery Techniques to CNS 521

24 Brain Delivery Using Nanotechnology 523
Huile Gao and Xinguo Jiang

25 Intranasal Delivery to the Central Nervous System 535
Lisbeth Illum

Part 7 Future Prospects in Blood-Brain Barrier

UNDERSTANDING AND DRUG DISCOVERY 567

26 Future Perspectives 569
N. Joan Abbott

Index 580