Abstract
The identification of orally active, small molecule antagonists of the α4β1 integrin, VLA-4, could lead to therapeutic agents with utility in a number of clinical settings, including asthma, multiple sclerosis and IBD. Starting from CDR3 sequences conserved among neutralizing α4 antibodies, peptides were identified that antagonized VLA-4 mediated adhesion in vitro. Through a series of structural modifications, these peptides evolved into small molecules that exhibited high potency and selectivity for VLA-4 in cell adhesion assays. Finally, through the optimization of physical and pharmacokinetic properties, compounds were identified that exhibited oral activity in animal models of asthma and multiple sclerosis.
Keywords: vla-4 antagonist, cell adhesion, pro-drug, multiple sclerosis, asthma
Current Topics in Medicinal Chemistry
Title: The Identification and Optimization of Orally Efficacious, Small Molecule VLA-4 Antagonists
Volume: 4 Issue: 14
Author(s): Donna M. Huryn, Andrei W. Konradi, Susan Ashwell, Stephen B. Freedman, Louis J. Lombardo, Michael A. Pleiss, Eugene D. Thorsett, Ted Yednock and Jeffrey D. Kennedy
Affiliation:
Keywords: vla-4 antagonist, cell adhesion, pro-drug, multiple sclerosis, asthma
Abstract: The identification of orally active, small molecule antagonists of the α4β1 integrin, VLA-4, could lead to therapeutic agents with utility in a number of clinical settings, including asthma, multiple sclerosis and IBD. Starting from CDR3 sequences conserved among neutralizing α4 antibodies, peptides were identified that antagonized VLA-4 mediated adhesion in vitro. Through a series of structural modifications, these peptides evolved into small molecules that exhibited high potency and selectivity for VLA-4 in cell adhesion assays. Finally, through the optimization of physical and pharmacokinetic properties, compounds were identified that exhibited oral activity in animal models of asthma and multiple sclerosis.
Export Options
About this article
Cite this article as:
Huryn M. Donna, Konradi W. Andrei, Ashwell Susan, Freedman B. Stephen, Lombardo J. Louis, Pleiss A. Michael, Thorsett D. Eugene, Yednock Ted and Kennedy D. Jeffrey, The Identification and Optimization of Orally Efficacious, Small Molecule VLA-4 Antagonists, Current Topics in Medicinal Chemistry 2004; 4 (14) . https://dx.doi.org/10.2174/1568026043387467
DOI https://dx.doi.org/10.2174/1568026043387467 |
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
-
Heparin - a Key Drug in the Treatment of the Circulatory Degenerative Diseases: Controlling its Action with Polymers
Current Pharmaceutical Design Modulation of MMP-9 Pathway by Lycopene in Macrophages and Fibroblasts Exposed to Cigarette Smoke
Inflammation & Allergy - Drug Targets (Discontinued) Adiponectin in Asthma: Implications for Phenotyping
Current Protein & Peptide Science Symptoms, Diagnosis, and Treatment of Cow's Milk Allergy
Current Pediatric Reviews Pharmacogenomics in the Americas: The Impact of Genetic Admixture
Current Drug Targets Lactones: Generic Inhibitors of Enzymes?
Mini-Reviews in Medicinal Chemistry Chemokines as Pharmacological Targets
Mini-Reviews in Medicinal Chemistry Mast Cell Tryptase β as a Target in Allergic Inflammation: An Evolving Story
Current Pharmaceutical Design Demystifying the ACE Polymorphism: From Genetics to Biology
Current Pharmaceutical Design The Dietary Paradox in Food Allergy: Yesterday's Mistakes, Today's Evidence and Lessons for Tomorrow
Current Pharmaceutical Design Intrahepatic Cholestasis of Pregnancy and Bile Acids Induced Lung Injury in Newborn Infants
Current Pediatric Reviews Future Targets for Immune Therapy in Colitis?
Endocrine, Metabolic & Immune Disorders - Drug Targets Acupuncture and Asthma: Ancient Technique that Survives Advances in Medicine
Current Respiratory Medicine Reviews Immunomodulatory Properties of Antibiotics
Current Molecular Pharmacology Phosphodiesterase 5 Inhibitors - Drug Design and Differentiation Based on Selectivity, Pharmacokinetic and Efficacy Profiles
Current Pharmaceutical Design Causes of Secretion Retention: Patient Factors, Ventilation, Devices, Drugs
Current Respiratory Medicine Reviews Hydrogen Sulfide: A New Tool to Design and Develop Drugs
Clinical Anti-Inflammatory & Anti-Allergy Drugs (Discontinued) Small Molecule Inhibitors of Phosphoinositide 3-Kinase (PI3K) δ and γ
Current Topics in Medicinal Chemistry Perspective on Nanoparticle Technology for Biomedical Use
Current Pharmaceutical Design Give Boron a Chance: Boron Containing Compounds Reach Ionotropic and Metabotropic Transmembrane Receptors
Mini-Reviews in Medicinal Chemistry