Abstract
Starting with a cyclic peptide of moderate potency as a VLA-4 antagonist, highly potent and conformationally defined cyclic peptides were developed incorporating a constrained tyrosine and an achiral Asp-Pro spacer. N-Acyl phenylalanine derivatives were also discovered to have VLA-4 antagonist activity. During the course of development of this series, we found that the active acylphenylalanines mimic the pharmacophores present in the cyclic peptides and hypothesized that they bind to the same site on VLA-4. This insight guided our optimization strategy. Based on the emerging SAR, as well as insights from the recent X-ray crystal structure of the integrin αvβ3 bound to a RGD containing cyclic peptide, we propose a binding model for these compounds.
Keywords: vla-4 antagonists, vascular cell adhesion molecule, asthma, inflammatory bowel disease, vcam/vla-4 interaction, acylphenylalanines, sar
Current Topics in Medicinal Chemistry
Title: The Discovery of VLA-4 Antagonists
Volume: 4 Issue: 14
Author(s): Jefferson W. Tilley, Li Chen, Achyutharao Sidduri and Nader Fotouhi
Affiliation:
Keywords: vla-4 antagonists, vascular cell adhesion molecule, asthma, inflammatory bowel disease, vcam/vla-4 interaction, acylphenylalanines, sar
Abstract: Starting with a cyclic peptide of moderate potency as a VLA-4 antagonist, highly potent and conformationally defined cyclic peptides were developed incorporating a constrained tyrosine and an achiral Asp-Pro spacer. N-Acyl phenylalanine derivatives were also discovered to have VLA-4 antagonist activity. During the course of development of this series, we found that the active acylphenylalanines mimic the pharmacophores present in the cyclic peptides and hypothesized that they bind to the same site on VLA-4. This insight guided our optimization strategy. Based on the emerging SAR, as well as insights from the recent X-ray crystal structure of the integrin αvβ3 bound to a RGD containing cyclic peptide, we propose a binding model for these compounds.
Export Options
About this article
Cite this article as:
Tilley W. Jefferson, Chen Li, Sidduri Achyutharao and Fotouhi Nader, The Discovery of VLA-4 Antagonists, Current Topics in Medicinal Chemistry 2004; 4 (14) . https://dx.doi.org/10.2174/1568026043387502
DOI https://dx.doi.org/10.2174/1568026043387502 |
Print ISSN 1568-0266 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4294 |
Call for Papers in Thematic Issues
Medicinal Chemistry Advancement in Life-Threatening Diseases
The current issue will highlight concise reports that specify ground-breaking insights, including the novel discovery of drug targets and their action mechanism or drugs of novel classes. These are projected to encourage medicinal chemistry future efforts to address the most challenging medical needs. The current issue highlights further efforts to ...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 Role of Lymphotoxin Receptor Signaling in Diseases
Current Molecular Medicine Origin and Biological Significance of Shed-Membrane Microparticles
Endocrine, Metabolic & Immune Disorders - Drug Targets A Nanotechnology-based Strategy to Increase the Efficiency of Cancer Diagnosis and Therapy: Folate-conjugated Gold Nanoparticles
Current Medicinal Chemistry Medicinal Chemistry of 2,2,4-Substituted Morpholines
Current Medicinal Chemistry Lipid Biomarkers in Alzheimer's Disease
Current Alzheimer Research GLP-1, Incretin Mimetics and DPP 4 Inhibitors: New Ways in the Treatment of Type 2 Diabetes
Current Medicinal Chemistry - Immunology, Endocrine & Metabolic Agents Identification of Genes for a Complex Trait: Examples from Hypertension
Current Pharmaceutical Biotechnology Photodynamic Therapy For Non-Melanoma Skin Cancers
Current Cancer Therapy Reviews Reactive Oxygen Species, Nitric Oxide and Hypertensive Endothelial Dysfunction
Current Hypertension Reviews Dual Inhibitors of Monoamine Oxidase and Cholinesterase for the Treatment of Alzheimer Disease
Current Topics in Medicinal Chemistry Liposome-Encapsulated Photosensitizers Against Bacteria
Recent Patents on Anti-Infective Drug Discovery Recent Approaches to Improve the Antitumor Efficacy of Temozolomide
Current Medicinal Chemistry Microbial Biotransformation: Recent Developments on Steroid Drugs
Recent Patents on Biotechnology Fundamentals in Cardiovascular Imaging Technologies
Current Pharmaceutical Design Clinical Consequences and Novel Therapy of Hyperphosphatemia: Lanthanum Carbonate for Dialysis Patients
Recent Patents on Cardiovascular Drug Discovery Mesenchymal Stromal Cells in Rheumatoid Arthritis: Biological Properties and Clinical Applications
Current Stem Cell Research & Therapy Potential Role of Polyphenols in the Prevention of Cardiovascular Diseases: Molecular Bases
Current Medicinal Chemistry Dietary Antioxidants and Oxidative Stress from a Human and Plant Perspective: A Review
Current Nutrition & Food Science Plasticity and Maintenance of Hematopoietic Stem Cells During Development
Recent Patents on Biotechnology Plant Natural Products in Anticancer Drug Discovery
Current Organic Chemistry