Blood-Brain Barrier: Bridging Options for Drug Discovery and Development

By Allan B. Haberman, PhD

Chapter 1
THE BLOOD-BRAIN BARRIER: A CHALLENGE FOR CNS DRUG DEVELOPMENT
1.1. Introduction to the BBB Bottleneck
1.2. Dearth of Drugs for CNS Diseases with High Unmet Need
Parkinson’s Disease
Multiple Sclerosis
1.3. New Approaches Needed to Overcome the BBB Hurdle
Tempting New CNS Targets…
…Belie an Underserved CNS Drug Market

Chapter 2
PHYSIOLOGY OF THE BLOOD-BRAIN BARRIER

2.1. Specialized Brain Capillaries Present Barriers to Diffusion
2.2. Transcranial Delivery of Drugs to Bypass the BBB

Chapter 3
DISCOVERY & DESIGN OF SMALL-MOLECULE DRUGS THAT CAN CROSS THE BLOOD-BRAIN BARRIER

3.1. Crossing the BBB via Passive Diffusion across the Brain Endothelium
The “Rule of Five” for Determining “Drug-Like” Properties
3.2. Action of Efflux Transporters in Inhibiting BBB Penetration
P-Glycoprotein (P-gp)
       Studies of P-gp Polymorphisms in Humans
Discovery and Design of Drugs That Use Nutrient Transporters to Cross the BBB
       Solute Carrier Transporters in Active Efflux from the BBB
3.3. Design of Small-Molecule Drugs That Use Carrier-Mediated Transport to Cross the BBB
Companies Involved in Developing Small-Molecule Drugs That Exploit Transporter Biology
       ArmaGen
       XenoPort
3.4. In Vivo Methods for Evaluating Drug Penetration of the BBB
Traditional In Vivo Methods for Determining BBB Penetrance
In Vivo Methods for Determining BBB Penetrance by Use of Imaging
       Positron Emission Tomography (PET)
       Magnetic Resonance Imaging (MRI)
       Functional Magnetic Resonance Imaging (fMRI)
3.5. In Vitro Methods for Determining BBB Penetrance
Cell Culture Models of the BBB
3.6. Use of Nanoparticle Technology to Enable BBB Penetration

Chapter 4
DISCOVERY & DESIGN OF LARGE-MOLECULE DRUGS THAT CAN CROSS THE BLOOD-BRAIN BARRIER

4.1. Exploiting Receptor-Mediated Transport in Design of Large-Molecule Drugs That Cross the BBB
Molecular Trojan Horses
4.2. Use of a Diphtheria Toxin Mimetic as a Molecular Trojan Horse for BBB Transport
4.3. Use of a Neurotropic Virus Glycoprotein Mimetic as a Molecular Trojan Horse for BBB Transport
4.4. Need for Basic Research to Find Additional Receptors That Can Be Exploited to Get Large-Molecule Drugs across the BBB
Genomics and Proteomics Research Aimed at Discovery of Novel BBB Transporters

Chapter 5
OUTLOOK FOR MEETING THE CHALLENGE OF THE BLOOD-BRAIN BARRIER IN DRUG DISCOVERY AND DEVELOPMENT

5.1. Blood-Brain Barrier Survey Results
5.2. Conclusions

Chapter 6
EXPERT INTERVIEWS

6.1. Pieter J. Gaillard, PhD
Founder & Chief Executive Officer
to-BBB, Leiden, The Netherlands

6.2. William M. Pardridge, MD
Chairman & Chief Scientific Officer
ArmaGen Technologies, Santa Monica, CA

6.3. Christopher L. Shaffer, PhD
Senior Principal Scientist, Neuroscience
Pharmacokinetics, Pharmacodynamics and Metabolism
Pfizer, Groton, CT

6.4. Noa Zerangue, PhD
Research Director
XenoPort, Santa Clara, CA

Chapter 7
SELECTED COMPANY PROFILES

7.1. Amgen
7.2. Cellial Technologies
7.3. GlaxoSmithKline
7.4. Merck & Co.
7.5. MethylGene
7.6. Pfizer
7.7. Wyeth
7.8. XenoPort

Appendix
INSIGHT PHARMA REPORTS BLOOD-BRAIN BARRIER SURVEY—January 2008

References

Company Index with Web Addresses