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• Strategies to develop small- and large-mol-ecule CNS drugs capable of crossing the blood-brain barrier (BBB)
• Interviews with leading researchers who are aggressively tackling the BBB challenge in CNS drug discovery and development
• Analysis of results from a Blood-Brain Barrier Survey, responded to by a range of companies involved in CNS research and drug discovery/development

CNS diseases are a major focus of the pharmaceutical industry, with CNS drugs representing some of its most successful products. These include Pfizer' s Zoloft (sertraline, for treatment of depression and certain types of anxiety disorders), Lilly' s Cymbalta (duloxetine, for treatment of depression) and Bristol-Myers Squibb' s/Otsuka' s Abilify (aripiprazole, for treatment of bipolar disorder and schizophrenia). However, drug discovery and development researchers experience difficulty developing CNS drugs that complete clinical trials and win regulatory approval - especially drugs which meet major unmet needs in the CNS area, such as Alzheimer' s disease. The vast majority of drugs fail to cross the BBB, which is causing a major bottleneck in successful development of CNS drug candidates.

This report reviews the discovery, design and development of small- and large-molecule drugs that can efficiently cross the BBB. This includes more traditional, medicinal chemistry-based methods, as well as approaches that exploit carrier-mediated transport (CMT) and receptor-mediated transport (RMT). Also covered in the report is use of nanoparticle technology to enable BBB penetration. Further, the report presents in vitro and in vivo assays as well as imaging methods to ascertain a drug' s ability to cross the BBB and reach its target.

The report includes results of a survey of researchers and executives - from corporate and academic organizations - who are active in the CNS drug development area. The survey explores their involvement in BBB-related technologies and programs. The survey results are discussed in terms of what they reveal about the current state of BBB research and the future potential for developing drugs that are able to cross it.

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