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

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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.  

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

  1. 1. Find Industry reports, Company profilesReportLinker and Market Statistics >> Get this Report Now by email!Blood-Brain Barrier: Bridging Options for Drug Discovery andDevelopmentPublished on May 2008 Report SummaryStrategies to develop small- and large-mol-ecule CNS drugs capable of crossing the blood-brain barrier (BBB) Interviews with leadingresearchers who are aggressively tackling the BBB challenge in CNS drug discovery and development Analysis of results from aBlood-Brain Barrier Survey, responded to by a range of companies involved in CNS research and drug discovery/development CNSdiseases are a major focus of the pharmaceutical industry, with CNS drugs representing some of its most successful products. Theseinclude 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 ofbipolar disorder and schizophrenia). However, drug discovery and development researchers experience difficulty developing CNSdrugs that complete clinical trials and win regulatory approval—especially drugs which meet major unmet needs in the CNSarea, such as Alzheimer’s disease. The vast majority of drugs fail to cross the BBB, which is causing a major bottleneck insuccessful 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. Thisincludes 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 theBBB and reach its target.The report includes results of a survey of researchers and executives—from corporate and academicorganizations—who are active in the CNS drug development area. The survey explores their involvement in BBB-relatedtechnologies and programs. The survey results are discussed in terms of what they reveal about the current state of BBB researchand the future potential for developing drugs that are able to cross it. Table of ContentChapter 1 - THE BLOOD-BRAIN BARRIER: A CHALLENGE FOR CNS DRUG DEVELOPMENT1.1. Introduction to the BBB Bottleneck1.2. Dearth of Drugs for CNS Diseases with High Unmet NeedParkinsons DiseaseMultiple Sclerosis1.3. New Approaches Needed to Overcome the BBB HurdleTempting New CNS TargetsBelie an Underserved CNS Drug MarketBlood-Brain Barrier: Bridging Options for Drug Discovery and Development (From Slideshare) Page 1/6
  2. 2. Find Industry reports, Company profilesReportLinker and Market Statistics >> Get this Report Now by email!Chapter 2 - PHYSIOLOGY OF THE BLOOD-BRAIN BARRIER2.1. Specialized Brain Capillaries Present Barriers to Diffusion2.2. Transcranial Delivery of Drugs to Bypass the BBBChapter 3 - DISCOVERY & DESIGN OF SMALL-MOLECULE DRUGS THAT CAN CROSS THE BLOOD-BRAIN BARRIER3.1. Crossing the BBB via Passive Diffusion across the Brain EndotheliumThe Rule of Five for Determining Drug-Like Properties3.2. Action of Efflux Transporters in Inhibiting BBB PenetrationP-Glycoprotein (P-gp) Studies of P-gp Polymorphisms in HumansDiscovery and Design of Drugs That Use Nutrient Transporters to Cross the BBB Solute Carrier Transporters in Active Efflux from the BBB3.3. Design of Small-Molecule Drugs That Use Carrier-Mediated Transport to Cross the BBBCompanies Involved in Developing Small-Molecule Drugs That Exploit Transporter Biology ArmaGen XenoPort3.4. In Vivo Methods for Evaluating Drug Penetration of the BBBTraditional In Vivo Methods for Determining BBB PenetranceIn 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 PenetranceCell Culture Models of the BBB3.6. Use of Nanoparticle Technology to Enable BBB PenetrationChapter 4- DISCOVERY & DESIGN OF LARGE-MOLECULE DRUGS THAT CAN CROSS THE BLOOD-BRAIN BARRIER4.1. Exploiting Receptor-Mediated Transport in Design of Large-Molecule Drugs That Cross the BBBMolecular Trojan Horses4.2. Use of a Diphtheria Toxin Mimetic as a Molecular Trojan Horse for BBB Transport4.3. Use of a Neurotropic Virus Glycoprotein Mimetic as a Molecular Trojan Horse for BBB Transport4.4. Need for Basic Research to Find Additional Receptors That Can Be Exploited to Get Large-Molecule Drugs across the BBBGenomics and Proteomics Research Aimed at Discovery of Novel BBB TransportersChapter 5 - OUTLOOK FOR MEETING THE CHALLENGE OF THE BLOOD-BRAIN BARRIER IN DRUG DISCOVERY ANDDEVELOPMENT5.1. Blood-Brain Barrier Survey Results5.2. ConclusionsChapter 6 - EXPERT INTERVIEWS6.1. Pieter J. Gaillard, PhDFounder & Chief Executive Officerto-BBB, Leiden, The NetherlandsBlood-Brain Barrier: Bridging Options for Drug Discovery and Development (From Slideshare) Page 2/6
  3. 3. Find Industry reports, Company profilesReportLinker and Market Statistics >> Get this Report Now by email!6.2. William M. Pardridge, MDChairman & Chief Scientific OfficerArmaGen Technologies, Santa Monica, CA6.3. Christopher L. Shaffer, PhDSenior Principal Scientist, NeurosciencePharmacokinetics, Pharmacodynamics and MetabolismPfizer, Groton, CT6.4. Noa Zerangue, PhDResearch DirectorXenoPort, Santa Clara, CAChapter 7 - SELECTED COMPANY PROFILES7.1. Amgen7.2. Cellial Technologies7.3. GlaxoSmithKline7.4. Merck & Co.7.5. MethylGene7.6. Pfizer7.7. Wyeth7.8. XenoPortTABLESTable 1.1. CNS Conditions Not Treatable With Current DrugsTable 3.1. Rule of Five for Oral Drugs vs. Rules for CNS-Penetrant DrugsTable 3.2. Substances Subject to P-gp Efflux from the BrainTable 4.1. Selected Receptor-Mediated Transport Systems Used for Development of Large-Molecule Drugs That Can Cross the BBBTable 4.2. ArmaGens Pipeline of Large-Molecule Drugs Based on Molecular Trojan Horse (MTH) TechnologyFIGURESFigure 2.1. Structure of Brain EndotheliumFigure 3.1. Role of SLC and ABC Transporters in Active Efflux of Drugs across the BBBFigure 3.2. Structures of L-DOPA and DopamineFigure 3.3. Co-Culture In Vitro Model of the BBBFigure 5.1. Respondents by Organization TypeFigure 5.2. Increased Involvement by Therapeutic AreaFigure 5.3. CNS Drugs in Early PipelineFigure 5.4. Pipeline IndicationsFigure 5.5. CNS Drug Development BottlenecksFigure 5.6. Increased Involvement by Drug TypeFigure 5.7. BBB R&D ProgramsFigure 5.8. BBB Programs: Small MoleculeFigure 5.9. BBB Technology DevelopmentFigure 5.10. BBB Programs: Large MoleculeFigure 5.11. Use of Imaging MethodsFigure 5.12. Types of Imaging MethodsBlood-Brain Barrier: Bridging Options for Drug Discovery and Development (From Slideshare) Page 3/6
  4. 4. Find Industry reports, Company profilesReportLinker and Market Statistics >> Get this Report Now by email!APPENDIX FIGURESFigure 1A. Respondents by Organization TypeFigure 2A. Respondents by Functional RoleFigure 3A. Respondents by Job TitleFigure 4A. CNS Product Areas PursuedFigure 5A. Change in CNS Drug InvolvementFigure 6A. Increased Involvement by Drug TypeFigure 7A. Increased Involvement by Therapeutic AreaFigure 8A. Estimated CNS Drug Launches, 2008/2009Figure 9A. CNS Drugs in Early PipelineFigure 10A. Pipeline IndicationsFigure 11A. CNS Drug Development BottlenecksFigure 12A. BBB R&D ProgramsFigure 13A. BBB Programs: Small MoleculeFigure 14A. BBB Programs: Large MoleculeFigure 15A. BBB Technology DevelopmentFigure 16A. Use of Imaging MethodsFigure 17A. Types of Imaging MethodsBlood-Brain Barrier: Bridging Options for Drug Discovery and Development (From Slideshare) Page 4/6
  5. 5. Find Industry reports, Company profilesReportLinker and Market Statistics >> Get this Report Now by email! Fax Order Form To place an order via fax simply print this form, fill in the information below and fax the completed form to: Europe, Middle East and Africa : + 33 4 37 37 15 56 Asia, Oceania and America : + 1 (805) 617 17 93 If you have any questions please visit http://www.reportlinker.com/notify/contact Order Information Please verify that the product information is correct and select the format(s) you require. Blood-Brain Barrier: Bridging Options for Drug Discovery and Development Product Formats Please select the product formats and the quantity you require. Digital Copy--USD 2 500.00 Quantity: _____ Corporate License--USD 5 000.00 Quantity: _____ Contact Information Please enter all the information below in BLOCK CAPITALS Title: Mr Mrs Dr Miss Ms Prof First Name: _____________________________ Last Name: __________________________________ Email Address: __________________________________________________________________________ Job Title: __________________________________________________________________________ Organization: __________________________________________________________________________ Address: __________________________________________________________________________ City: __________________________________________________________________________ Postal / Zip Code: __________________________________________________________________________ Country: __________________________________________________________________________ Phone Number: __________________________________________________________________________ Fax Number: __________________________________________________________________________Blood-Brain Barrier: Bridging Options for Drug Discovery and Development (From Slideshare) Page 5/6
  6. 6. Find Industry reports, Company profilesReportLinker and Market Statistics >> Get this Report Now by email! Payment Information Please indicate the payment method, you would like to use by selecting the appropriate box. Payment by credit card Card Number: ______________________________________________ Expiry Date __________ / _________ CVV Number _____________________ Card Type (ex: Visa, Amex…) _________________________________ Payment by wire transfer Crédit Mutuel RIB : 10278 07314 00020257701 89 BIC : CMCIFR2A IBAN : FR76 1027 8073 1400 0202 5770 189 Payment by check UBIQUICK SAS 16 rue Grenette – 69002 LYON, FRANCE Customer signature:   Please note that by ordering from Reportlinker you are agreeing to our Terms and Conditions at http://www.reportlinker.com/index/terms Please fax this form to: Europe, Middle East and Africa : + 33 4 37 37 15 56 Asia, Oceania and America : + 1 (805) 617 17 93Blood-Brain Barrier: Bridging Options for Drug Discovery and Development (From Slideshare) Page 6/6

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