Ion Channel Modulator Pipelines: Targets and Agents in Development Overview

Table of Contents

CHAPTER 1 INTRODUCTION 1

• 1.1. What Are Ion Channels?
• 1.2. Channel Activation
  • Ligand-Gated
  • Voltage-Gated
  • Conformational States
  • Accessory Proteins and Subunits
  • Specificity and Function
• 1.3. Opportunity

CHAPTER 2 TARGET CLASSES

• 2.1. Overview
• 2.2. Classification
• 2.3. Voltage-Gated Channels
  • Chloride
  • ClC Channels
  • ClCa
  • CFTR
  • Sodium
  • Calcium
  • Potassium
  • KV Channels
  • KCa Channels
  • Kir Channels
  • K2P Channels
  • Degenerins
  • Non-Specific Cation Channels
• 2.4. Ligand-Gated Channels
  • Cyclic Nucleotide (CNGA, CNGB, and HCN)
  • Nicotinic Receptors
  • GABAA
  • Glutamate
  • NMDA
  • AMPA
  • Kainate
  • Glycine
  • 5-HT3 Receptors
  • Purinergic
  • Transient Receptor Potential Channels
  • TRPV
  • TRPM
  • TRPA

CHAPTER 3 TECHNICAL CONSIDERATIONS

• 3.1. Introduction
• 3.2. Target Distribution
• 3.3. Ion Channel Structures
  • Structural Biology
• 3.4. What to Target
  • Multiple States
  • Accessory Proteins
  • The hERG Channel
• 3.5. Screening Issues
• 3.6. Non-Electrical Methods
  • FLIPR Assays
  • Isotopic Flux
  • FRET
• 3.7. High-Throughput Electrophysiology

CHAPTER 4 COMMERCIALLY SUCCESSFUL ION CHANNEL MODULATORS

• 4.1. Overview
• 4.2. L-Type Calcium Channel Blockers
• 4.3. Antidiabetic KATP Modulators
• 4.5. GABA Analogs
• 4.6. Antiarrhythmic Agents (Potassium Channel Blockers)
• 4.7. Anticonvulsants (Sodium Channel Blockers)
• 4.8. 5-HT3 Antagonists
• 4.9. Nicotinic Receptors
• 4.10. Other Ion Channel Modulators

CHAPTER 5 ION CHANNEL MODULATORS IN CLINICAL DEVELOPMENT

• 5.1. Overview
  • By Company
  • Abbott
  • AstraZeneca
  • Eli Lilly
  • GlaxoSmithKline
  • Pfizer
  • sanofi-aventis
  • By Channel Type
  • By Indication
  • Late-Stage Development Compounds
  • Tedisamil
  • Vernakalant
  • Dronedarone
  • Eslicarbazepine
  • Indiplon
  • NGX-4010
  • Zucapsaicin
  • Amifampridine
  • Fampridine
  • SK-310
• 5.2. Phase III
  • Gastrointestinal Disorders
  • Arverapamil
  • Crofelemer
  • Anxiety
  • TIK-101
  • PD-332334
  • Pagoclone
  • Epilepsy
  • Perampanel
  • Retigabine
  • Other CNS Indications
  • Dimebolin
  • RPI-78M
  • Safinamide
  • Cystic Fibrosis
  • VX-770
• 5.3. Phase II
  • CNS Conditions
  • Alzheimer' s Disease
  • Pain
  • Schizophrenia
  • Anxiety and Depression
  • Parkinson' s Disease
  • Epilepsy
  • Other CNS Conditions
  • Peripheral Conditions
  • Inflammatory Diseases
  • Cystic Fibrosis
  • Cardiovascular Disease
  • Gastrointestinal Disease
  • Oncology
  • Glaucoma and Tinnitus
• 5.4. Phase I
  • GABA
  • Glutamate Receptors
  • Nicotinic Receptors
  • Voltage-Gated Channels
  • TRPV1
  • Other
• 5.5. Outlook 93

CHAPTER 6 COMPANY PROFILES

• 6.1. Introduction
• 6.2. Leading Major Companies
  • AstraZeneca
  • Eli Lilly
  • GlaxoSmithKline
  • Merck & Co.
  • Novartis
  • Pfizer
  • sanofi-aventis
• 6.3. Selected Biotechnology Companies
  • Aurora Biomed
  • CalciMedica
  • Cellectricon
  • CytoCentrics
  • EPIX Pharmaceuticals
  • Evotec
  • Flyion
  • Hydra Biosciences
  • Icagen
  • iOnGen
  • Lectus Therapeutics
  • Nanion Technologies
  • Neurion Pharmaceuticals
  • Neuromed Pharmaceuticals
  • NeuroSearch
  • Newron Pharmaceuticals
  • Parion Sciences
  • Targacept
  • Xention

CHAPTER 7 OUTLOOK

• 7.1. Commercial Outlook
• 7.2. Scientific Outlook

CHAPTER 8 EXPERT INTERVIEWS

CHAPTER 9 RESULTS FROM INSIGHT PHARMA REPORTS' ION CHANNELS SURVEY, JULY 2009

• Question 1. Please classify your organization.
• Question 2. Under what functional area do your responsibilities fall?
• Question 3. What disease areas do you feel will see significant treatment advances as a result of ion channel modulator development over the next five years?
• Question 4. The major thrust of current efforts aimed at ion channel modulators appears to be focused on CNS conditions, with some activity aimed at heart disease and limited interest in other conditions. Is this overlooking other potential targets?
• Question 5. There has been a recent explosion in interest in the development of TRP channel modulators. Do you think that we are likely to see many modulators of channels other than TRPV1 enter development in the near term?
• Question 6. In your opinion, what type(s) of ion channels have the greatest potential as drug targets?
• Question 7. My organization currently targets the following type(s) of ion channels...
• Question 8. In what areas of ion channel development are further advances going to be the most critical?
• Question 9. Has there been an upsurge of research activity on ion channel targets since the emergence of improved knowledge of their molecular structure and newer screening methods?
• Question 10. In your opinion, has the lack of reliable screening assays been the major factor in decisions of large pharma to avoid the pursuit of many ion channel targets?
• Question 11. In your opinion, what is currently the greatest barrier to successful development of ion channel modulators?
• Question 12. Do you think that the low conductance of many types of ion channels has been a major barrier to both their study and the
• identification of selective modulators?
• Question 13. How has your organization' s level of activity changed in the past five years in terms of developing ion channel modulators?
• Question 14. Does your organization plan to change its level of involvement with ion channels over the next three years?
• Question 15. Do you have any additional observations about the discovery and development of ion channel modulators?

REFERENCES 133

COMPANY INDEX WITH WEB ADDRESSES 149

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