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Published by: CHI Insight Pharma Reports
Published: Sep. 1, 2009 - 154 Pages
Table of Contents
- CHAPTER 1
- INTRODUCTION
- 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
- 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
- COMPANY INDEX WITH WEB ADDRESSES
- ABOUT CAMBRIDGE HEALTHTECH INSTITUTE
AbstractIon channels represent a significant opportunity to address an underexploited class of therapeutic targets. Nearly 150 novel ion channel modulators are reported to be in clinical development. This report examines:
- Ion channel modulators in clinical development and their potential
- Improved molecular understanding of ion channel structure and cellular activity
- High-throughput screening methods for identification of novel modulators
- Prospects for ion channel modulators and commercial successes to date• Pipeline activities, expert views, and survey results
Ion Channel Modulator Pipelines: Targets and Agents in Development provides a comprehensive analysis of the ion channel modulator pipeline, breaking it down by company, ion channel type, and therapeutic indication. A number of interesting trends are revealed: Major pharmaceutical companies currently only account for just over one-third of all the ion channel modulators in development. The range of channel types targeted by ion channel modulators in development is relatively limited and heavily skewed toward a few channel types. Eighty percent of these ion channel modulators are being developed for diverse CNS indications.
This report also analyzes the approximately 100 ion channel modulators that have been approved for clinical use. These drugs have generated considerable revenues: Even though generic forms of many of these agents are now available, sales of these branded drugs were around $20 billion in 2007. However, relatively few of these were developed using channel-based screening approaches, and many were identified with little or no knowledge of their mechanism of action.
To date, ion channel modulators have been identified by various means, relatively few of which have so far been focused on direct screening of compounds for their activity on the channel(s) of interest. The past few years have seen significant developments that facilitate the identification of novel ion channel modulators. These improvements in screening methods should lead to more selective agents being identified and progressing into clinical development. We also examine other technical considerations when attempting to modulate ion channels, such as target distribution throughout the body, and the structure of ion channels and their multiple states (e.g., each state of the ion channel offers a different conformation for a potential ligand to recognize and thus any ion channel provides multiple potential targets).
Ion Channel Modulator Pipelines: Targets and Agents in Development concludes with a commercial and scientific outlook, expert interviews, and results from a survey gauging trends, current practices, and views on ion channel-focused R&D activity.
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