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

Table of Contents

• 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

• 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

• 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

• 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

• 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

• 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

• 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

• INSIGHT PHARMA REPORTS BLOOD-BRAIN BARRIER SURVEY - January 2008

References

Company Index with Web Addresses