Author: Peter Norman, PhD, MBA
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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