Abstract
Proteases constitute one of the largest potential drug target enzyme families,
with 647 human gene products incorporating protease sequences and mutated
proteases having been identified. In addition, there are many more proteases
found in viruses, bacteria, and parasites, which are also potential drug
targets. The therapeutic promise of protease inhibitors has been most clearly
demonstrated by angiotensin-converting enzyme (ACE) and HIV drugs.
Developments reviewed in this report indicate that more protease inhibitors,
several having significant commercial potential, will reach the market over
the next three to four years.
Examples are:
- Oral antithrombotic agents to supplant warfarin
- Novel renin-targeting hypertension candidates
- Better-tolerated, oral, anti-hepatitis C agents
- Treatment of Alzheimer' s disease via γ-secretase
- Cathepsin K inhibition for osteoporosis treatment
- DPP IV inhibitors for managing type II diabetes
Inhibition of protease activity modulates physiological functions, either by
reducing the formation of undesirable peptide mediators or by enhancing the
beneficial effects of peptides by preventing their catabolism. A significant
number of proteases have some potential as drug targets. Because of the
disparate nature of the physiological roles of proteases and the diverse
nature of their substrates, it has proved less straightforward to identify the
number of human proteases that are potential drug targets in comparison to
GPCRs or protein kinases. Proteases include drug targets for HIV and the
clotting cascade as well as degradative enzymes such as elastase and
dipeptidyl peptidases such as DPP IV.
Many viral, bacterial, and parasitic proteases are also potential drug targets
and, due to their lower homology to their mammalian orthologs, offer target
opportunities to identify selective inhibitors that have minimal
cross-reactivity with mammalian proteases. In addition to these proteases,
some 77 mutated proteases have been identified to date which often contribute
to hereditary diseases and, therefore, represent target opportunities.
Protease Inhibitors: Innovation Drives Drug Pipeline seeks to provide a
comprehensive assessment of those protease inhibitors that have been reported
as in active development in late 2008, and to highlight the areas on which
pharmaceutical and biotechnology companies are currently focusing their
research efforts. To clearly understand the complexities of protease inhibitor
development, this report reviews the various classes of proteases following
the systematic classifications that have evolved, while considering some of
the technical problems that have complicated protease inhibitor development.
Protease Inhibitors: Innovation Drives Drug Pipeline highlights the
commercial successes that have been achieved to date, primarily with respect
to ACE inhibitors and HIV protease inhibitors. The report then considers
development pipelines by therapeutic area rather than by specific classes of
protease targets due to the diversity of potential therapeutic indications in
which protease inhibitors are of potential value. The report also includes
brief profiles of the protease inhibitor activity within major pharmaceutical
companies and selected biotechnology companies.
Protease Inhibitors: Innovation Drives Drug Pipeline looks at some 20
protease inhibitors, and three fixed-dose combinations in advanced development
that are expected to be submitted for FDA approval in the period between late
2008 and 2013. This analysis clearly indicates that the successful development
of protease inhibitors offers significant therapeutic and commercial benefits.
Several of these protease inhibitors are expected to achieve major commercial
success. The report also focuses on a considerable number of protease
inhibitors that are in development and may reach NDA submission status by the
end of this period.
Table of Contents
Chapter 1
- INTRODUCTION TO THE WORLD OF PROTEASES
- 1.1. What Is a Protease?
- Proteases, Proteinases, Exopeptidases, and Endopeptidases
- Proteolytic Cascades
- 1.2. The Renin-Angiotensin-Aldosterone System - RAAS
- 1.3. Coagulation Cascade
- 1.4. Multiplicity of Potential Drug Targets
Chapter 2
- OVERVIEW OF PROTEASE TARGET CLASSES
- 2.1. Overview
- 2.2. Classification
- 2.3. Aspartic Proteases
- A01 Family
- A22 Subfamily
- 2.4. Serine Proteases
- S01 Proteases
- Coagulation Factors
- Kallikreins
- Complement and uPA
- Trypsin and Chymotrypsin
- Tryptase and Elastase
- Other S01 Serine Proteases
- Heat Shock Proteins
- Dipeptidyl-Peptidases
- Other Serine Proteases
- 2.5. Threonine Proteases
- 2.6. Cysteine Proteases
- Caspases
- Cathepsins
- Calpains
- Ubiquitin-Specific Peptidases
- Other Cysteine Proteases
- 2.7. Metalloproteases
- Aminopeptidases
- Carboxypeptidase
- Endopeptidases
- Matrix Metalloproteases
- ADAM Family
- ADAM-TS Family
- Other Metalloproteases
- 2.8. Non-mammalian Proteases
- Bacterial Proteases
- Viral Proteases
- Parasitic Proteases
Chapter 3
- PROTEASES AS DRUG TARGETS
- 3.1. Introduction
- 3.2. Target Distribution
- 3.3. Protease Structures
- 3.4. Mechanism of Inhibition
- 3.5. Screening Issues
- 3.6. Summary
Chapter 4
- Protease Inhibitor Drugs
- 4.1. Overview
- 4.2. ACE Inhibitors
- 4.3. HIV Protease Inhibitors
- 4.4. Emerging Protease Inhibitors
- Sitagliptin
- Vildagliptin
- Aliskerin
Chapter 5
- PROTEASE INHIBITORS IN CLINICAL DEVELOPMENT
- 5.1. Overview
- 5.2. By Company
- 5.3. By Indication
- Cardiovascular Disease
- Renin Inhibitors
- Coagulation Cascade
- Factor Xa Inhibitors
- Indirect Factor Xa Inhibitors
- Idraparinux
- Idrabiotaparinux
- Octaparine
- M-enoxaparin and M-118
- Direct Factor Xa Inhibitors in Phase II
- Otamixaban
- YM-510
- DU-1766
- Eribaxaban
- Betrixaban (PRT-054021)
- TAK-442
- LY-517717
- Thrombin Inhibitors
- Thrombin Inhibitors in Phase II
- Other Peptidase Inhibitors
- LCZ-696
- Daglutril
- TPC-806
- TTP-889
- Metabolic Diseases
- DPP IV Inhibitors
- Alogliptin
- Saxagliptin
- Linagliptin
- Dutogliptin
- DPP IV Inhibitors in Phase II
- PF-734200
- Melogliptin (GRC-8200)
- TA-6666 & MP-51
- AMG-222
- SYR-472 & SYR-619
- KRP-104 & LC-15-0444
- Carmegliptin
- CNS Diseases
- General Protease Inhibitors
- Beta-Secretase (BACE1) Inhibitors
- Gamma-Secretase Inhibitors
- NIC5-15
- Semagacestat
- Tarenflurbil
- Caspase Inhibitors
- Inflammatory and Musculoskeletal Diseases
- COPD
- Elastase Inhibitors
- Depelestat
- AZD-9668 & BAY 71-9678
- MMP-12 Inhibitors
- Rheumatoid Arthritis
- Osteoarthritis
- Allergic Diseases
- Chymase and Tryptase Inhibitors
- MMP-9 Inhibitors
- Osteoporosis
- Cathepsin K Inhibitors
- Odanacatib
- ONO-5334
- MIV-701
- VEL-0230
- Oncology
- Protease and Metalloprotease Inhibitors
- Tigapotide
- Aderbasib
- XL-784
- R-4733
- Viral Infections
- Hepatitis C
- NS3 Protease Inhibitors
- Ciluprevir
- ITMN-191
- ACH-1625
- IDX-136 & IDX-316
- TMC-435350
- MK-7009
- Telaprevir
- VX-500 & VX-813
- Boceprevir
- Caspase Inhibitors
- LB-84451
- Emricasan
- EP-1013
- CTS-1027
- HIV
- Bacterial and Parasitic Infections
- 5.4. Outlook
Chapter 6
- COMPANY PROFILES
- 6.1. Introduction
- Major Companies
- AstraZeneca
- Bayer
- Boehringer Ingelheim
- Bristol-Myers Squibb
- Eli Lilly
- Merck
- Novartis
- Pfizer
- Roche
- sanofi-aventis
- Schering Plough
- Takeda
- 6.2. Selected Biotechnology Companies
- Ambrilia Biopharma
- Amura Therapeutics
- Idenix Pharmaceuticals
- Incyte
- Medivir AB
- Sequoia Pharmaceuticals
- Speedel Holding AG
- Velcura Therapeutics
- Vertex Pharmaceuticals
- Virobay
Chapter 7
- NEAR-TERM COMMERCIAL PROSPECTS
- 7.1. Introduction
- 7.2. Cardiovascular Diseases
- 7.3. Diabetes
- 7.4. Other Indications
- 7.5. Conclusions
Chapter 8
- EXPERT INTERVIEWS
- 8.1. Mark Whittaker PhD, Senior Vice President Drug Discovery, Evotec OAI, Abingdon, UK, and Scientific Director of Evotec' s Services Divisions
- 8.2. Professor Bertil Samuelsson PhD, Vice President, Research, Medivir AB, Huddinge, Sweden
References
- Company Index with Web Addresses
