Abstract
Cardiovascular disease (CVD) is responsible for ∼27% of deaths worldwide, with 80% of these occuring in developing countries. Hypertension is one of the most important treatable factors in the prevention of CVD. Angiotensin-I converting enzyme (ACE) is a two-domain dipeptidylcarboxypeptidase that is a key regulator of blood pressure as a result of its critical role in the reninangiotensin- aldosterone and kallikrien-kinin systems. Consequently, ACE is an important drug target in the treatment of CVD. ACE is primarily known for its ability to cleave angiotensin-I to the vasoactive octapeptide angiotensin-II, but is also able to cleave a number of other substrates including the vasodilator bradykinin and N-acetyl-seryl-aspartyl-lysyl-proline (acetyl-SDKP), a physiological modulator of hematopoiesis. Numerous ACE inhibiors are available clinically, and these are generally effective in treating hypertension. However some adverse effects are associated with ACE inhibition, such as the persistent dry cough and the potentially fatal angioedema. The solution of ACE crystal structures over the last decade has facilitated rational drug design which has contributed to the development of domain-selective ACE inhibitors, the most notable of which include RXP407 (N-domain) and RXPA380 (C-domain), which in principle may herald new therapeutic approaches for ACE inhibition. Additionally, dual inhibitors to ACE and other targets such as neprilysin, endothelin converting enzyme and chymase have been developed. The success of ACE inhibitors has also led to the search for novel inhibitors in food and natural products and the structure guided screening of such libraries may well reveal a number of new ACE inhibitors.
Keywords: Angiotensin-I converting enzyme, cardiovascular disease, crystal structure, domain selective inhibitors, hypertension, structurebased drug design, zinc metallopeptidase, dipeptidylcarboxypeptidase, vasodilator bradykinin
Current Medicinal Chemistry
Title: Structure Based Drug Design of Angiotensin-I Converting Enzyme Inhibitors
Volume: 19 Issue: 6
Author(s): C. S. Anthony, G. Masuyer, E. D. Sturrock and K. R. Acharya
Affiliation:
Keywords: Angiotensin-I converting enzyme, cardiovascular disease, crystal structure, domain selective inhibitors, hypertension, structurebased drug design, zinc metallopeptidase, dipeptidylcarboxypeptidase, vasodilator bradykinin
Abstract: Cardiovascular disease (CVD) is responsible for ∼27% of deaths worldwide, with 80% of these occuring in developing countries. Hypertension is one of the most important treatable factors in the prevention of CVD. Angiotensin-I converting enzyme (ACE) is a two-domain dipeptidylcarboxypeptidase that is a key regulator of blood pressure as a result of its critical role in the reninangiotensin- aldosterone and kallikrien-kinin systems. Consequently, ACE is an important drug target in the treatment of CVD. ACE is primarily known for its ability to cleave angiotensin-I to the vasoactive octapeptide angiotensin-II, but is also able to cleave a number of other substrates including the vasodilator bradykinin and N-acetyl-seryl-aspartyl-lysyl-proline (acetyl-SDKP), a physiological modulator of hematopoiesis. Numerous ACE inhibiors are available clinically, and these are generally effective in treating hypertension. However some adverse effects are associated with ACE inhibition, such as the persistent dry cough and the potentially fatal angioedema. The solution of ACE crystal structures over the last decade has facilitated rational drug design which has contributed to the development of domain-selective ACE inhibitors, the most notable of which include RXP407 (N-domain) and RXPA380 (C-domain), which in principle may herald new therapeutic approaches for ACE inhibition. Additionally, dual inhibitors to ACE and other targets such as neprilysin, endothelin converting enzyme and chymase have been developed. The success of ACE inhibitors has also led to the search for novel inhibitors in food and natural products and the structure guided screening of such libraries may well reveal a number of new ACE inhibitors.
Export Options
About this article
Cite this article as:
S. Anthony C., Masuyer G., D. Sturrock E. and R. Acharya K., Structure Based Drug Design of Angiotensin-I Converting Enzyme Inhibitors, Current Medicinal Chemistry 2012; 19 (6) . https://dx.doi.org/10.2174/092986712799034950
DOI https://dx.doi.org/10.2174/092986712799034950 |
Print ISSN 0929-8673 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-533X |
Call for Papers in Thematic Issues
Advances in Medicinal Chemistry: From Cancer to Chronic Diseases.
The broad spectrum of the issue will provide a comprehensive overview of emerging trends, novel therapeutic interventions, and translational insights that impact modern medicine. The primary focus will be diseases of global concern, including cancer, chronic pain, metabolic disorders, and autoimmune conditions, providing a broad overview of the advancements in ...read more
Approaches to the treatment of chronic inflammation
Chronic inflammation is a hallmark of numerous diseases, significantly impacting global health. Although chronic inflammation is a hot topic, not much has been written about approaches to its treatment. This thematic issue aims to showcase the latest advancements in chronic inflammation treatment and foster discussion on future directions in this ...read more
Cellular and Molecular Mechanisms of Non-Infectious Inflammatory Diseases: Focus on Clinical Implications
The Special Issue covers the results of the studies on cellular and molecular mechanisms of non-infectious inflammatory diseases, in particular, autoimmune rheumatic diseases, atherosclerotic cardiovascular disease and other age-related disorders such as type II diabetes, cancer, neurodegenerative disorders, etc. Review and research articles as well as methodology papers that summarize ...read more
Chalcogen-modified nucleic acid analogues
Chalcogen-modified nucleosides, nucleotides and oligonucleotides have been of great interest to scientific research for many years. The replacement of oxygen in the nucleobase, sugar or phosphate backbone by chalcogen atoms (sulfur, selenium, tellurium) gives these biomolecules unique properties resulting from their altered physical and chemical properties. The continuing interest in ...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
-
The Indian Pediatric HIV Epidemic: A Systematic Review
Current HIV Research Multifunctional Anti-Cancer Nano-Platforms are Moving to Clinical Trials
Current Drug Metabolism Adamantane – A Lead Structure for Drugs in Clinical Practice
Current Medicinal Chemistry Contemporary Pharmacologic Management of Heart Failure with Reduced Ejection Fraction: A Review
Current Cardiology Reviews Bridging the Gap Between Chemistry and Biotechnology - Large Molecules with Potential, How Could Biotechnology Complement Chemistry?
Current Organic Chemistry ADR in Journals: Are They Translated into Regulatory Frameworks?
Current Drug Safety Neuro-AIDS: Current Status and Challenges to Antiretroviral Drug Therapy (ART) for Its Treatment
Current Drug Therapy Desensitization Protocol for Rituximab-Induced Serum Sickness
Current Drug Safety Management of Hypertension-Journey from Single Drug Therapy to Multitargeted Ligand Therapy: A Clinical Overview
Current Clinical Pharmacology Hypertensive Pharmacogenomics in African Americans
Current Pharmacogenomics Future Preventive and Therapeutic Targets for Transfusion-Related Acute Lung Injury
Current Pharmaceutical Design The Complement Cascade: New Avenues in Stroke Therapy
Current Vascular Pharmacology Pharmacological Interactions on Blood Pressure Control in Arterial Hypertension, An Issue not to be Overlooked
Cardiovascular & Hematological Disorders-Drug Targets Allergen-Induced Inflammation
Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry Novel Drugs for Inflammatory Lung Diseases
Current Medicinal Chemistry - Anti-Inflammatory & Anti-Allergy Agents Drug Development and the Importance of Ethnicity: Lessons from Heart Failure Management and Implications for Hypertension
Current Pharmaceutical Design Adverse Drug Reaction Labelling for Atomoxetine, Methylphenidate and Modafinil: Comparison of Product Information for Oral Formulations in Australia, Denmark and the United States
Current Drug Safety The Renin-Angiotensin System: The Role of Inhibitors, Blockers, and Genetic Polymorphisms in the Treatment and Prevention of Heart Failure
Current Vascular Pharmacology Life Threatening and Fatal Contrast Media Reactions: Pathomechanisms, Diagnosis, Prevention and Drug Management
Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry Prevalence of Intestinal Parasites among Patients with Chronic Urticaria in Northern Iran
Infectious Disorders - Drug Targets