Blood–Brain Barrier in Drug Discovery – Optimizing Brain Exposure of CNS Drugs and Minimizing Brain Side Effects for Peripheral Drugs
Optimizing Brain Exposure of CNS Drugs and Minimizing Brain Side Effects for Peripheral Drugs
Samenvatting
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
Specificaties
Inhoudsopgave
<p>Preface xiii</p>
<p>1 Introduction and Overview 1<br /> Li Di and Edward H. Kerns</p>
<p>Part 1 Pharmacokinetics of Brain Exposure 5</p>
<p>2 Pharmacokinetics of CNS Penetration 7<br /> Andreas Reichel</p>
<p>3 Free Drug Hypothesis for CNS Drug Candidates 42<br /> Xingrong Liu and Cuiping Chen</p>
<p>4 Species Differences and Impact of Disease State on BBB—66<br /> Jean–Marie Nicolas</p>
<p>Part 2 Mechanisms of Drugs Across the Blood Brain Barrier 95</p>
<p>5 Passive Diffusion Permeability of the BBB Examples and SAR—97<br /> Scott Summerfield, Phil Jeffrey, Jasminder Sahi, and Liangfu Chen</p>
<p>6 Establishment of P–Glycoprotein Structure Transport Relationships to Optimize CNS Exposure in Drug Discovery 113<br /> Jerome H. Hochman, Sookhee N. Ha, and Robert P. Sheridan</p>
<p>7 Uptake Transport at the BBB Examples and SAR—125<br /> Ziqiang Cheng and Qian Liu</p>
<p>8 Transport of Protein and Antibody Therapeutics across the Blood Brain Barrier 146<br /> William M. Pardridge</p>
<p>Part 3 Predicting and Measuring Brain Exposure of Drugs 167</p>
<p>9 In Silico Tools for Predicting Brain Exposure of Drugs 169<br /> Hongming Chen, Susanne Winiwarter, and Ola Engkvist</p>
<p>10 In Vitro Assays for Assessing BBB Permeability: Artificial Membrane and Cell Culture Models 188<br /> Alex Avdeef, Mária A. Deli, and Winfried Neuhaus</p>
<p>11 Human–Based In Vitro Brain Endothelial Cell Models 238<br /> Hannah K. Wilson and Eric V. Shusta</p>
<p>12 Methods for Assessing Brain Binding 274<br /> Li Di and Cheng Chang</p>
<p>13 In Vivo Studies of Brain Exposure in Drug Discovery 284<br /> Edward H. Kerns</p>
<p>14 PBPK Modeling Approach for Predictions of Human CNS Drug Brain Distribution 296<br /> Elizabeth C.M. de Lange</p>
<p>15 PK/PD Modeling of CNS Drug Candidates 324<br /> Johan Gabrielsson, Stephan Hjorth, and Lambertus A. Peletier</p>
<p>16 Microdialysis to Assess Free Drug Concentration in Brain 351<br /> William Kielbasa and Robert E. Stratford, Jr.</p>
<p>17 Imaging Techniques for Central Nervous System (CNS) Drug Discovery 365<br /> Lei Zhang and Anabella Villalobos</p>
<p>Part 4 Modulating Brain Penetration of Leads During Drug Discovery 385</p>
<p>18 Designing CNS Drugs for Optimal Brain Exposure 387<br /> Zoran Rankovic</p>
<p>19 Case Studies of CNS Drug Optimization Medicinal Chemistry and CNS Biology Perspectives 425<br /> Kevin J. Hodgetts</p>
<p>20 Designing Peripheral Drugs for Minimal Brain Exposure 446<br /> Peter Bungay, Sharan Bagal, and Andy Pike</p>
<p>21 Case Studies of Non–CNS Drugs to Minimize Brain Penetration Nonsedative Antihistamines 463<br /> Andrew Crowe</p>
<p>Part 5 Case Studies in CNS Drug Discovery 483</p>
<p>22 Case Study 1: The Discovery and Development of Perampanel 485<br /> Antonio Laurenza, Jim Ferry, Haichen Yang, Shigeki Hibi, Takahisa Hanada, and Andrew Satlin</p>
<p>23 Case Study 2: The Discovery and Development of the Multimodal Acting Antidepressant Vortioxetine 505<br /> Christoffer Bundgaard, Alan L. Pehrson, Connie Sánchez, and Benny Bang–Andersen</p>
<p>Part 6 Drug Delivery Techniques to CNS 521</p>
<p>24 Brain Delivery Using Nanotechnology 523<br /> Huile Gao and Xinguo Jiang</p>
<p>25 Intranasal Delivery to the Central Nervous System 535<br /> Lisbeth Illum</p>
<p>Part 7 Future Prospects in Blood–Brain Barrier</p>
<p>UNDERSTANDING AND DRUG DISCOVERY 567</p>
<p>26 Future Perspectives 569<br /> N. Joan Abbott</p>
<p>Index 580</p>