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
Chemistry Based on Natural Products for Therapeutic Purposes
The development of new pharmaceuticals for a wide range of medical conditions has long relied on the identification of promising natural products (NPs). There are over sixty percent of cancer, infectious illness, and CNS disease medications that include an NP pharmacophore, according to the Food and Drug Administration. Since NP ...read more
Current Trends in Drug Discovery Based on Artificial Intelligence and Computer-Aided Drug Design
Drug development discovery has faced several challenges over the years. In fact, the evolution of classical approaches to modern methods using computational methods, or Computer-Aided Drug Design (CADD), has shown promising and essential results in any drug discovery campaign. Among these methods, molecular docking is one of the most notable ...read more
Drug Discovery in the Age of Artificial Intelligence
In the age of artificial intelligence (AI), we have witnessed a significant boom in AI techniques for drug discovery. AI techniques are increasingly integrated and accelerating the drug discovery process. These developments have not only attracted the attention of academia and industry but also raised important questions regarding the selection ...read more
From Biodiversity to Chemical Diversity: Focus of Flavonoids
Flavonoids are the largest group of polyphenols, plant secondary metabolites arising from the essential aromatic amino acid phenylalanine (or more rarely from tyrosine) via the phenylpropanoid pathway. The flavan nucleus is the basic 15-carbon skeleton of flavonoids (C6-C3-C6), which consists of two phenyl rings (A and B) and a heterocyclic ...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
-
Targeting DNA Associated Processes for Cancer Therapy by the Use of SELEX and Anti-gene Approaches - When Selection Meets Rational Design
Medicinal Chemistry Reviews - Online (Discontinued) Biologics as Treatment for Systemic Lupus: Great Efforts, Sobering Results, New Challenges
Current Drug Discovery Technologies Cardiovascular Proteomics
Current Proteomics Rheumatological Manifestations in Diabetes Mellitus
Current Diabetes Reviews Monoclonal Antibodies as Cancer Therapeutics
Recent Patents on Biotechnology Natural Products with Antiangiogenic and Antivasculogenic Mimicry Activity
Mini-Reviews in Medicinal Chemistry Homology Modeling and Antagonist Binding Site Study of the Human Histamine H2 Receptor
Medicinal Chemistry Molecular Imaging with Small Animal PET/CT
Current Medical Imaging New Targets for the Modulation of Radiation Response - Selective Inhibition of the Enzyme Cyclooxygenase 2
Current Medicinal Chemistry - Anti-Cancer Agents Apoptotic Potency of Angiostatic Compounds in the Treatment of Cancer
Current Pharmaceutical Biotechnology Advances Towards The Discovery of GPR55 Ligands
Current Medicinal Chemistry The Molecular Mechanisms and Rational Design of Anti-Diabetic Vanadium Compounds
Current Topics in Medicinal Chemistry Uncovering the Diversification of Tissue Engineering on the Emergent Areas of Stem Cells, Nanotechnology and Biomaterials
Current Stem Cell Research & Therapy Pharmacological Inhibition of Protein Tyrosine Phosphatase 1B: A Promising Strategy for the Treatment of Obesity and Type 2 Diabetes Mellitus
Current Medicinal Chemistry Ruthenium Complexes as Anticancer Agents
Current Medicinal Chemistry “Smart” Nanocarriers: A New Paradigm for Tumor Targeting Drug Delivery Systems
Drug Delivery Letters Phage-Displayed Combinatorial Peptide Libraries in Fusion to β-Lactamase as Reporter for an Accelerated Clone Screening: Potential Uses of Selected Enzyme-Linked Affinity Reagents in Downstream Applications
Combinatorial Chemistry & High Throughput Screening The Use of Intravenous Aminobisphosphonates for the Treatment of Pagets Disease of Bone
Mini-Reviews in Medicinal Chemistry The Current Status of Novel PET Radio-Pharmaceuticals in Radiotherapy Treatment Planning of Glioma
Current Pharmaceutical Biotechnology The Role of Thiols and Disulfides on Protein Stability
Current Protein & Peptide Science