Abstract
Thrombin, a plasma serine protease, plays a key role not only in coagulation and hemostasis but in thrombosis, restenosis and atherosclerosis. Thrombin activates platelets, endothelium, inflammatory cells and smooth muscle cells. The cellular action of thrombin is mediated by specific G-protein coupled thrombin receptors called proteinase-activated receptors (protease-activated receptor or PARs). Among the three thrombin receptors, PAR1 is the primary thrombin receptor in human and animal cells with an exception of non-primate platelets. An increased thrombin generation and PAR1 expression are observed on cells within atherosclerotic plaque and thrombus and following vascular injury. Animal studies with PAR1 deficient mice and small molecule antagonists indicate an important role of PAR1 in thrombosis and restenosis and thus the therapeutic potential of a PAR1 antagonist in treating these diseases. Development of a thrombin receptor tethered ligand analog binding assay led to the discovery of several different series of potent, nonpeptide small molecular antagonists of PAR1. These antagonists are PAR1 selective and inhibit most of the cellular effects of thrombin. A PAR1 antagonist has an advantage over a direct thrombin inhibitor since it does not inhibit enzymatic action of thrombin in the coagulation cascade with the consequent minimal bleeding side-effects, unlike a direct thrombin inhibitor. In addition, the emerging evidence for the role of PAR1 in various inflammatory diseases suggests as yet unexplored therapeutic potentials of PAR1 antagonists in various inflammatory diseases.
Keywords: proteinase-activated receptor, par1, thrombin, platelet, thrombosis
Current Pharmaceutical Design
Title: Development of Proteinase-Activated Receptor 1 Antagonists as Therapeutic Agents for Thrombosis, Restenosis and Inflammatory Diseases
Volume: 9 Issue: 28
Author(s): Ho-Sam Ahn, Samuel Chackalamannil, George Boykow, Michael P. Graziano and Carolyn Foster
Affiliation:
Keywords: proteinase-activated receptor, par1, thrombin, platelet, thrombosis
Abstract: Thrombin, a plasma serine protease, plays a key role not only in coagulation and hemostasis but in thrombosis, restenosis and atherosclerosis. Thrombin activates platelets, endothelium, inflammatory cells and smooth muscle cells. The cellular action of thrombin is mediated by specific G-protein coupled thrombin receptors called proteinase-activated receptors (protease-activated receptor or PARs). Among the three thrombin receptors, PAR1 is the primary thrombin receptor in human and animal cells with an exception of non-primate platelets. An increased thrombin generation and PAR1 expression are observed on cells within atherosclerotic plaque and thrombus and following vascular injury. Animal studies with PAR1 deficient mice and small molecule antagonists indicate an important role of PAR1 in thrombosis and restenosis and thus the therapeutic potential of a PAR1 antagonist in treating these diseases. Development of a thrombin receptor tethered ligand analog binding assay led to the discovery of several different series of potent, nonpeptide small molecular antagonists of PAR1. These antagonists are PAR1 selective and inhibit most of the cellular effects of thrombin. A PAR1 antagonist has an advantage over a direct thrombin inhibitor since it does not inhibit enzymatic action of thrombin in the coagulation cascade with the consequent minimal bleeding side-effects, unlike a direct thrombin inhibitor. In addition, the emerging evidence for the role of PAR1 in various inflammatory diseases suggests as yet unexplored therapeutic potentials of PAR1 antagonists in various inflammatory diseases.
Export Options
About this article
Cite this article as:
Ahn Ho-Sam, Chackalamannil Samuel, Boykow George, Graziano P. Michael and Foster Carolyn, Development of Proteinase-Activated Receptor 1 Antagonists as Therapeutic Agents for Thrombosis, Restenosis and Inflammatory Diseases, Current Pharmaceutical Design 2003; 9 (28) . https://dx.doi.org/10.2174/1381612033453884
DOI https://dx.doi.org/10.2174/1381612033453884 |
Print ISSN 1381-6128 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4286 |
Call for Papers in Thematic Issues
"Tuberculosis Prevention, Diagnosis and Drug Discovery"
The Nobel Prize-winning discoveries of Mycobacterium tuberculosis and streptomycin have enabled an appropriate diagnosis and an effective treatment of tuberculosis (TB). Since then, many newer diagnosis methods and drugs have been saving millions of lives. Despite advances in the past, TB is still a leading cause of infectious disease mortality ...read more
Current Pharmaceutical challenges in the treatment and diagnosis of neurological dysfunctions
Neurological dysfunctions (MND, ALS, MS, PD, AD, HD, ALS, Autism, OCD etc..) present significant challenges in both diagnosis and treatment, often necessitating innovative approaches and therapeutic interventions. This thematic issue aims to explore the current pharmaceutical landscape surrounding neurological disorders, shedding light on the challenges faced by researchers, clinicians, and ...read more
Emerging and re-emerging diseases
Faced with a possible endemic situation of COVID-19, the world has experienced two important phenomena, the emergence of new infectious diseases and/or the resurgence of previously eradicated infectious diseases. Furthermore, the geographic distribution of such diseases has also undergone changes. This context, in turn, may have a strong relationship with ...read more
Melanoma and Non-Melanoma Skin Cancer Treatment: Standard of Care and Recent Advances
In this thematic issue, we aim to provide a standard of care of the diagnosis and treatment of melanoma and non-melanoma skin cancer. The editor will invite authors from different countries who will write review articles of melanoma and non-melanoma skin cancers. The Diagnosis, Staging, Surgical Treatment, Non-Surgical Treatment all ...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
- Announcements
Related Articles
-
Microcirculation in Sepsis: New Perspectives
Current Vascular Pharmacology N-acetylcysteine Exerts Protective Effects and Prevents Lung Redox Imbalance and Peroxynitrite Generation in Endotoxemic Rats
Medicinal Chemistry Adenosine and Adenosine Receptors in the Pathomechanism and Treatment of Respiratory Diseases
Current Medicinal Chemistry Treatment of Diabetic Foot Ulcer: An Overview Strategies for Clinical Approach
Current Diabetes Reviews Psoriatic Arthritis and its Novel Therapeutics
Current Rheumatology Reviews Oligonucleotide-Based Molecular Therapy for Restenosis after Angioplasty
Current Drug Targets Role of Vascular Endothelial Growth Factor in Kidney Disease
Current Vascular Pharmacology Usefulness of Magnetic Resonance Imaging in Cardiac and Enovascular Intervention
Current Medical Imaging Recent Highlights on Molecular Hybrids Potentially Useful in Central Nervous System Disorders
Mini-Reviews in Medicinal Chemistry A Brief Overview on Chemistry and Biology of Benzoxepine
Letters in Drug Design & Discovery Recent Advances in the Treatment of Neurogenic Erectile Dysfunction
Recent Patents on CNS Drug Discovery (Discontinued) Editorial [Hot Topic: Applications of Angiotensin Converting Enzyme Inhibitors and of Angiotensin II Receptor Blockers in Pharmacology and Therapy: An Update (Executive Editor: Agostino Molteni)]
Current Pharmaceutical Design Fetal Undernutrition and the Programming of Blood Pressure
Current Nutrition & Food Science Closed-loop Neuropharmacology for Epilepsy: Distant Dream or Future Reality?
Current Neuropharmacology Pharmacologic Therapy for Cardiovascular Risk Reduction in Patients with the Metabolic Syndrome
Current Pharmaceutical Design Critical Roles for Bradykinin and Prostanoids in Acute Inflammatory Reactions: A Search Using Experimental Animal Models
Current Drug Targets - Inflammation & Allergy Cardiorenal Consequences of Atherosclerosis and Statins Therapy: From the Past to the Future
Current Pharmaceutical Design Purification and Characterization of a Novel Lectin with Antiphytovirus Activities from the wild Mushroom Paxillus involutus
Protein & Peptide Letters TEM8 Targeted Cancer Therapy
Anti-Cancer Agents in Medicinal Chemistry Endothelins and the Role of Endothelin Antagonists in the Management of Posttraumatic Vasospasm
Current Pharmaceutical Design