Abstract
Physiologic clotting is a defensive action. The new cell-based model of hemostasis proposes three steps – initiation, amplification and propagation – occurring on specific cell surfaces to generate a thrombus in a tightly regulated manner. The initiation phase relies on key players including tissue factor (TF), factor VIIa (fVIIa), platelets, Ca2+, phospholipids, and factor X/Xa (fX/fXa). Exposure of TF on sub-endothelial and other blood cells triggers a coagulation response, which may have to be inhibited to prevent a deleterious thrombotic effect. Inhibiting TF-initiated coagulation, akin to ‘nipping coagulation in the bud’, is predicted to have major advantages, including a more efficient separation of the antithrombotic and hemorrhagic responses. The availability of crystal structures of TF, fVIIa and TF – fVIIa complex makes structure-based drug design feasible. Although no initiation phase small molecule inhibitor has reached the clinic as yet, several molecules have displayed promise. We discuss recent results on the discovery of inhibitors of the initiation phase with special emphasis on peptides, peptidomimetics and organic small molecules.
Keywords: Anticoagulants, coagulation, factor VIIa, tissue factor, thrombin, factor Xa, enzyme inhibition, small molecule inhibitors
Cardiovascular & Hematological Agents in Medicinal Chemistry
Title: Recent Research Developments in the Direct Inhibition of Coagulation Proteinases – Inhibitors of the Initiation Phase
Volume: 6 Issue: 4
Author(s): Brian L. Henry and Umesh R. Desai
Affiliation:
Keywords: Anticoagulants, coagulation, factor VIIa, tissue factor, thrombin, factor Xa, enzyme inhibition, small molecule inhibitors
Abstract: Physiologic clotting is a defensive action. The new cell-based model of hemostasis proposes three steps – initiation, amplification and propagation – occurring on specific cell surfaces to generate a thrombus in a tightly regulated manner. The initiation phase relies on key players including tissue factor (TF), factor VIIa (fVIIa), platelets, Ca2+, phospholipids, and factor X/Xa (fX/fXa). Exposure of TF on sub-endothelial and other blood cells triggers a coagulation response, which may have to be inhibited to prevent a deleterious thrombotic effect. Inhibiting TF-initiated coagulation, akin to ‘nipping coagulation in the bud’, is predicted to have major advantages, including a more efficient separation of the antithrombotic and hemorrhagic responses. The availability of crystal structures of TF, fVIIa and TF – fVIIa complex makes structure-based drug design feasible. Although no initiation phase small molecule inhibitor has reached the clinic as yet, several molecules have displayed promise. We discuss recent results on the discovery of inhibitors of the initiation phase with special emphasis on peptides, peptidomimetics and organic small molecules.
Export Options
About this article
Cite this article as:
Henry L. Brian and Desai R. Umesh, Recent Research Developments in the Direct Inhibition of Coagulation Proteinases – Inhibitors of the Initiation Phase, Cardiovascular & Hematological Agents in Medicinal Chemistry 2008; 6 (4) . https://dx.doi.org/10.2174/187152508785909519
DOI https://dx.doi.org/10.2174/187152508785909519 |
Print ISSN 1871-5257 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-6182 |
Call for Papers in Thematic Issues
Medicinal Plants with Beneficial Properties on Diabetes and Hypertension
Diabetes and hypertension are real scourges of the 21st century. It is imperative to act in order to find innovative solutions to this problem. Taking medications such as hypoglycemic and antihypertensive drugs may aggravate certain underlying comorbidities, such as chronic kidney disease and cardiovascular disease. This significant drawback therefore requires ...read more
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
Related Articles
-
Bioorganic Compounds Produced by the Fungus Monascus and their Use in Health Sciences and Medicine
Mini-Reviews in Organic Chemistry Developing Practical Therapeutic Strategies that Target Protein SUMOylation
Current Drug Targets Immunomodulatory Drugs as a Therapy for Multiple Myeloma
Current Pharmaceutical Biotechnology Redox Homeostasis, Bioactive Agents and Transduction Therapy
Current Signal Transduction Therapy Buccal Delivery of Methimazole as an Alternative Means for Improvement of Drug Bioavailability: Permeation Studies and Matrix System Design
Current Pharmaceutical Design Study on the Formation Mechanisms of the Degradation Products of Salvianolic Acid A
Current Analytical Chemistry 3-Phenyl-1H-Indole-5-Sulfonamides: Structure-Based Drug Design of a Promising Class of Carbonic Anhydrase Inhibitors
Current Pharmaceutical Design Pharmacokinetic and Pharmacodynamic Properties of Anti-VEGF Drugs After Intravitreal Injection
Current Drug Metabolism Insights on the Neuromodulatory Propensity of Selaginella (Sanjeevani) and its Potential Pharmacological Applications
CNS & Neurological Disorders - Drug Targets 3D-QSAR Methodologies and Molecular Modeling in Bioinformatics for the Search of Novel Anti-HIV Therapies: Rational Design of Entry Inhibitors
Current Bioinformatics Contrast Agents in X-Ray Computed Tomography and Its Applications in Oncology
Anti-Cancer Agents in Medicinal Chemistry The Anti-Breast Cancer Effects of Green-Synthesized Zinc Oxide Nanoparticles Using Carob Extracts
Anti-Cancer Agents in Medicinal Chemistry Role of Diagnostic Ultrasound in Patient Selection for Stroke Intervention
Recent Patents on CNS Drug Discovery (Discontinued) Pituitary Stem Cells Drop Their Mask
Current Stem Cell Research & Therapy Polyphenols from Red Wine Modulate Immune Responsiveness: Biological and Clinical Significance
Current Pharmaceutical Design The Immunomodulatory Potential of Selected Bioactive Plant-Based Compounds in Breast Cancer: A Review
Anti-Cancer Agents in Medicinal Chemistry Experimental Diabetes Mellitus Down-Regulates Large-Conductance Ca2+- Activated K+ Channels in Cerebral Artery Smooth Muscle and Alters Functional Conductance
Current Neurovascular Research Triggering PIK3CA Mutations in PI3K/Akt/mTOR Axis: Exploration of Newer Inhibitors and Rational Preventive Strategies
Current Pharmaceutical Design Targeting PPAR Isoforms Following CNS Injury
Current Drug Targets The Current Role and Therapeutic Targets of Vitamin D in Gastrointestinal Inflammation and Cancer
Current Pharmaceutical Design