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Protease Inhibitors: Innovation Drives Drug Pipeline

CHI Insight Pharma Reports
February 1, 2009
156 Pages - SKU: CHI2210677

Abstract Table of Contents Related Reports

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 ã-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.

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
Tables and Figures: Figures:; Figure 1.1. Schematic of the Renin-Angiotensin-Aldosterone System; Figure 1.2. Schematic of the Coagulation Cascade; Figure 5.1. Development Status of Protease Inhibitors being Developed by Major Pharmaceutical Companies; Tables:; Table 2.1. Human Degradome by Catalytic Class; Table 2.2. A02 Family Aspartic Proteases; Table 2.3. A01 Family Aspartic Proteases; Table 2.4. A22 Family Aspartic Proteases; Table 2.5. S01 Serine Proteases that Affect the Coagulation Cascade; Table 2.6. S01 Kallikrein Serine Proteases; Table 2.7. S01 S01 Serine Proteases of the Complement System.; Table 2.8. S01 Trypsin-like Serine Proteases; Table 2.9. S01 Tryptase and Elastase-like Serine Proteases; Table 2.10. Other S01 Family Serine Proteases; Table 2.11. Sx2 Family Serine Proteases; Table 2.12. S09 Family Serine Proteases; Table 2.13. S08 Family Serine Proteases; Table 2.14. Serine Proteases from Other than the S01, Sx2, S08, and S09 Families; Table 2.15. Threonine Proteases; Table 2.16. Caspase Cysteine Proteases; Table 2.17. Cathepsin Cysteine Proteases; Table 2.18. Calpain Cysteine Proteases; Table 2.19. Ubiquitin Cysteine Proteases; Table 2.20. Non C01, C02, C14, and C19 Cysteine Proteases; Table 2.21. Aminopeptidase Metalloproteases; Table 2.22. Carboxypeptidase Metalloproteases; Table 2.23. Endopeptidase Metalloproteases; Table 2.24. Matrix Metalloproteases; Table 2.25. ADAM Family Metalloproteases; Table 2.26. ADAM-TS Family Metalloproteases; Table 2.27. M16, M19, M22, and M28 Family Metalloproteases; Table 2.28. Meta Zinc Metalloproteases; Table 4.1. Marketed ACE Inhibitors and 2007 Sales Revenues; Table 4.2. Marketed HIV Protease Inhibitors and 2007 Sales Revenues; Table 5.1. Protease Inhibitors in Development for Cardiovascular Diseases Other than Thrombosis; Table 5.2. Direct and Indirect Factor Xa Inhibitors in Development; Table 5.3. Thrombin Inhibitors in Development; Table 5.4. DPP-IV Inhibitors in Development; Table 5.5. Protease Inhibitors in Development for CNS Disorders; Table 5.6. Protease Inhibitors in Development for Inflammatory or Musculoskeletal Diseases; Table 5.7. Cathepsin K Inhibitors in Development; Table 5.8. Protease Inhibitors in Development for the Treatment of Cancer and Angiogenic Disorders; Table 5.9. Protease Inhibitors in Development for the Treatment of Viral Infections; Table 6.1. AstraZeneca's Protease Inhibitor Pipeline; Table 6.2. Bayer's Protease Inhibitor Pipeline; Table 6.3. Boehringer Ingelheim's Protease Inhibitor Pipeline; Table 6.4. Bristol-Myers Squibb's Protease Inhibitor Pipeline; Table 6.5. Eli Lilly's Protease Inhibitor Pipeline; Table 6.6. Merck's Protease Inhibitor Pipeline; Table 6.7. Novartis' Protease Inhibitor Pipeline; Table 6.8. Pfizer's Protease Inhibitor Pipeline; Table 6.9. Roche's Protease Inhibitor Pipeline; Table 6.10. sanofi-aventis' Protease Inhibitor Pipeline; Table 6.11. Schering Plough's Protease Inhibitor Pipeline; Table 6.12. Takeda's Protease Inhibitor Pipeline; Table 7.1. Protease Inhibitors in Late-stage Development and Anticipated NDA Filing Dates

Protease Inhibitors: Innovation Drives Drug Pipeline

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