TRANSMEMBRANE TRANSPORTERS
High sales, high potential
Executive Summary
Chapter 1 Why target transporters?
1.1 Introduction
1.2 Functions of transporters
1.3 Transport mechanisms
1.4 The TC classification system for transporters
1.4.1 Transporter classes
1.4.2 Transporter families and superfamilies
1.5 Progress in structure elucidation
1.6 Top-selling transporter-targeted drugs
Chapter 2 Ion transporters
2.1 Introduction
2.3 Ion pumps
2.3.1 Overview
2.3.2 Ion pumps as drug targets
2.3.2.1 The ABC Superfamily
2.3.2.2 The P-ATPase Superfamily
2.4 Ion channels
2.4.1 Overview
2.4.1.1 Structural architectures
2.4.1.2 Screening technologies
2.4.2 Sodium channels as drug targets
2.4.2.1 The Voltage-gated Ion Channel Superfamily
2.4.2.2 Other voltage-gated channels
2.4.2.3 The Epithelial Na+ Channel Family
2.4.3 Potassium channels as drug targets
2.4.3.1 The Voltage-gated Ion Channel Superfamily
2.4.3.2 The Inward Rectifier K+ Channel Family
2.4.3.3 The Ca2+-activated Auxiliary Subunit Sloá Family
2.4.4 Calcium channels as drug targets
2.4.4.1 The Voltage-gated Ion Channel Superfamily
2.4.4.2 Other calcium channels
2.4.5 Chloride channels as drug targets
2.4.5.1 The Epithelial Chloride Channel Family
2.4.5.2 The Chloride Channel Family
2.5 Solute (ion) carriers
2.5.1 Overview
2.5.2 Solute carriers as drug targets
2.5.2.1 The Cation-Chloride Cotransporter Family
2.5.2.2 The Major Facilitator Superfamily
2.5.2.3 The Cation:Proton Antiporter1 Family
2.5.2.4 Other solute carriers
2.6 Miscellaneous targets
Chapter 3 Neurotransmitter-binding transporters
3.1 Introduction
3.1.1 Major neurotransmitters and their functions
3.1.2 Role of membrane transporters in neurotransmission
3.2 Ionotropic receptors as drug targets
3.2.1 Overview
3.2.2 The Ligand-gated Ion Channel Family
3.2.2.1 GABA-A receptors
3.2.2.2 5-HT3 receptor
3.2.2.3 Nicotinic acetylcholine receptor
3.2.2.4 Glycine receptor
3.2.3 The Glutamate-gated Ion Channel Family
3.2.3.1 NMDA receptor
3.2.3.2 AMPA receptor
3.2.3.3 Kainate receptor
3.2.4 The ATP-gated Cation Channel Family
3.3 Solute carriers as drug targets
3.3.1 Overview
3.3.2 The Neurotransmitter:Sodium Symporter Family
3.3.2.1 Serotonin transporter
3.3.2.2 Noradrenalin transporter
3.3.2.3 Dopamine transporter
3.3.2.4 GABA transporters
3.3.2.5 Glycine transporter
3.3.3 The Dicarboxylate/Amino Acid:Cation Symporter Family
3.3.4 The Major Facilitator Superfamily
Chapter 4 Lipid, bile acid, and carbohydrate transporters
4.1 Lipid and bile acid transporters as drug targets
4.1.1 Introduction
4.1.2 The ABC Superfamily
4.1.2.1 ABCA1 transporter
4.1.2.2 ABCG5 and ABCG8 transporters
4.1.3 The Bile Acid:Na+ Symporter Family
4.1.3.1 IBAT transporter
4.1.4 The Putative Fatty Acid Transporter Family
4.1.4.1 FATP4 transporter
4.2 Carbohydrate transporters as drug targets
4.2.1 Introduction
4.2.2 The Major Facilitator Superfamily
4.2.2.1 GLUT4 transporter
4.2.3 The Solute:Sodium Symporter Family
4.2.3.1 SGLT1 and SGLT2 transporters
Chapter 5 Other areas of research
5.1 Transporters in cancer drug resistance
5.1.1 Role of MDR-ABC transporters
5.1.1.1 MDR1 transporter
5.1.1.2 MRP1 transporter
5.1.1.3 MXR transporter
5.1.1.4 Other transporters
5.1.2 Pharmacological modulation of MDR transporters
5.2 Transporters in ADME/Tox
5.2.1 ABC transporter assays for ADME/Tox prediction
5.2.2 Ion channel assays for cardiac toxicity
5.3 Transporters in infectious diseases
5.4 Transporters in drug delivery
Chapter 6 Profiles of selected companies
6.1 Abbott
6.2 Akzo Nobel
6.3 Astellas
6.4 AstraZeneca
6.5 Bayer
6.6 Biovail
6.7 Boehringer Ingelheim
6.8 Bristol-Myers Squibb
6.9 Cortex Pharmaceuticals
6.10 Daiichi Sankyo
6.11 Elan
6.12 Eli Lilly
6.13 GlaxoSmithKline
6.14 Hoffman-La Roche
6.15 ICagen
6.16 Johnson & Johnson
6.17 Lundbeck
6.18 Merck KGaA
6.19 Merck & Co
6.20 Mitsubishi Pharma
6.21 NeuroSearch
6.22 Novartis
6.23 Novo Nordisk
6.24 NPS Pharmaceuticals
6.25 Pfizer
6.26 Sanofi-Aventis
6.27 Sepracor
6.28 Servier
6.29 Takeda
6.30 Wyeth
Chapter 7 Market Considerations and Forecasts
7.1 Introduction
7.2 The Survey
7.2.1 Preliminary remarks
7.2.2 Questions and answers
7.2.3 Conclusions
7.3 The World Pharmaceutical Market
7.4 The Market for Transporter-Targeted Products
7.4.1 Cardiovascular Market
7.4.2 Central Nervous System (CNS) Market
7.4.3 Alimentary/Metabolic Market
7.5 Transporter Drug R&D: Leading Indications
7.6 Transporter Drug R&D: Leading Companies
7.7 Transporter Drug Companies and Applications
7.8 Transporter Drug Companies and Targets
7.9 Transporter Market Analysis and Forecasts to 2010
Chapter 8 Trends and Opportunities
8.1 Transporters embraced by big pharma
8.2 Over 100 transporter targets under investigation
8.3 The most popular targets and indications
8.4 Opportunities in analgesia
8.5 Next generation ion channel modulators
8.6 Next generation ligand-gated ion channel modulators
8.7 Next generation neurotransmitter reuptake inhibitors
8.8 Next generation glutamate-gated ion channel modulators
8.9 Exploring new transporter targets
8.10 Towards gene family-based transporter drug discovery
8.11 Expanding applications outside drug discovery
EXECUTIVE SUMMARY
Amongst the top 100 best-selling drugs in the US in 2004, transporters
represent the most abundant class of targets. There are at least 1,302
transporter drugs (both launched drugs and drugs in development) in the
portfolios of 326 companies worldwide. These drugs target ion
transporters, neurotransmitter-binding transporters, lipid, carbohydrate
and other transporters. Altogether more than 100 transporter targets are
under investigation. These are some of the findings which emerged from an
analysis of the top-selling drugs on the US market and a survey of launched
and in-development drugs targeting transporters based on Pharmaprojects, a
leading drug R&D database. Most respondents from the pharmaceutical
industry responding to an on-line survey conducted for this report felt
that transporters, alongside protein kinases, were commercially the most
promising targets available to the drug industry.
The transporter-targeted drug market was worth $107.2 billion in 2005,
17.8% of the total pharmaceutical market in that year. It is forecast to
reach $153.8 billion in 2010, a compound annual growth rate (CAGR) of 7.5%,
when it will be worth 16.3% of the total drug market. The leading
indications are cardiovascular and CNS.
In reviewing individual transporter targets in this report we have adopted
a gene family-based approach, whereby each transporter is discussed within
the context of the family to which it belongs. Transporter families are at
the heart of the TC classification system approved by the International
Union of Biochemistry and Molecular Biology. Following an introduction to
each transporter family, individual transporters are discussed as well as
drugs targeting them, their stage of development and indications for which
they are being developed. For the most part, family membership implies
similar function and mechanism. Future exploitation of transporter drug
targets will benefit from knowledge gained about families to which they
belong and other successfully exploited family members.
The vast majority of transporter targets are ion transporters and
neurotransmitter-binding transporters. Homeostatic regulation of ionic
gradients across cellular membranes is critical for most biological
functions. Transporters involved in ion homeostasis include ion pumps, ion
channels, and carrier-type transporters. Of particular importance are
voltage-gated ion channels which have a crucial role in excitable tissues
such as nerve and cardiac muscle. Neurotransmitter-binding transporters
regulate the levels of most neurotransmitters in the CNS.
Neurotransmitter-gated ion channels rapidly convert the chemical signal of
presynaptically released neurotransmitter into a postsynaptic electrical
signal. The actions of neurotransmitters are terminated by high affinity
carrier proteins.
Interest in lipid transporters arises from their likely involvement in the
control of blood lipid levels. Glucose transporters have possible utility
in treating diabetes. MDR transporters, responsible for multidrug
resistance associated with cancer treatment failure, and
pathogen-associatedtransporter targets. ABC transporters are being
utilized for in vitro ADME/tox predition, and hERG ion channel screening
can evaluate new drugs for cardiac safety. Transport mechanisms have also
began to be exploited to improve drug delivery.
This report profiles 30 companies which are key players in the world
transporter-targeted drug market. These companies have the greatest
numbers of transporter-targeted drugs in their portfolios. Information is
provided about transporter-targeted drugs in each company's drug portfolio.
