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 |
- 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
-
Targeting Role of Glioma Stem Cells for Glioblastoma Multiforme
Current Medicinal Chemistry Protective Effects of Dietary Flavonoids in Diabetic Induced Retinal Neurodegeneration
Current Drug Targets Adenosine in the Inflamed Gut: A Janus Faced Compound
Current Medicinal Chemistry Mutations of Mitochondrial DNA in Atherosclerosis and Atherosclerosis-Related Diseases
Current Pharmaceutical Design Comparing the Molecular Pharmacology of CGRP and Adrenomedullin
Current Protein & Peptide Science Melatonin and Melatoninergic Drugs as Therapeutic Agents: Ramelteon and Agomelatine, the Two Most Promising Melatonin Receptor Agonists
Recent Patents on Endocrine, Metabolic & Immune Drug Discovery Interactions of the Aryl Hydrocarbon Receptor with Inflammatory Mediators:Beyond CYP1A Regulation
Current Drug Metabolism Hematoma Expansion: Clinical and Molecular Predictors and Corresponding Pharmacological Treatment
Current Drug Targets Dipeptidyl-Peptidase IV (DPP IV/CD26)-Activated Prodrugs: A Successful Strategy for Improving Water Solubility and Oral Bioavailability
Current Medicinal Chemistry Calpains: Attractive Targets for the Development of Synthetic Inhibitors
Current Topics in Medicinal Chemistry Cell Sheet Technology for Heart Failure
Current Pharmaceutical Biotechnology Drug-induced Inhibition and Trafficking Disruption of ion Channels: Pathogenesis of QT Abnormalities and Drug-induced Fatal Arrhythmias
Current Cardiology Reviews Proteasome Inhibitors in Cancer Therapy
Current Drug Targets Bone Marrow Stem Cell Therapy for Myocardial Angiogenesis
Current Vascular Pharmacology Role of Iodine, Selenium and Other Micronutrients in Thyroid Function and Disorders
Endocrine, Metabolic & Immune Disorders - Drug Targets The Association between Metabolic Syndrome and Serum Levels of Adiponectin and High Sensitive C Reactive Protein in Gorgan
Endocrine, Metabolic & Immune Disorders - Drug Targets Stimuli Responsive Nanoparticles for Controlled Anti-cancer Drug Release
Current Medicinal Chemistry Novel Marine-Derived Anti-Cancer Agents
Current Pharmaceutical Design Sustained Delivery of Interferons by Micro- and Nanosystems
Recent Patents on Materials Science Characterization and Antihypertensive Effect of the Complex of (-)-β- pinene in β-cyclodextrin
Current Pharmaceutical Biotechnology