Author: Peter Norman, PhD, MBA
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
MK-8141
SPP-635
Coagulation Cascade
Factor Xa Inhibitors
Rivaroxaban
Apixaban
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
Dabigatran
AZD-0837
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
SLV-334
DP-b99
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
Cathepsin S Inhibitors
Osteoarthritis
Aggrecanase Inhibitors
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
HIV Protease Inhibitors
MK-8122
SPI-256
DG-17
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