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
-
Sulfur-Containing Compounds in Protecting Against Oxidant-Mediated Lung Diseases
Current Medicinal Chemistry CpG Oligodeoxynucleotides: A Novel Therapeutic Approach For Atopic Disorders
Current Drug Targets - Inflammation & Allergy Development of Colon Specific Microspheres of Flurbiprofen for Inflammatory Bowel Disease
Current Drug Delivery The Possible Adverse Effects of Intramuscular Botulinum Toxin Injections and their Management
Current Drug Safety Molecular Basis of the Anti-Inflammatory Effects of Terpenoids
Inflammation & Allergy - Drug Targets (Discontinued) Chalcones as Versatile Synthons for the Synthesis of 5- and 6-membered Nitrogen Heterocycles
Current Organic Chemistry The Long and Winding Road to Convert an Antimicrobial Compound into an Antimicrobial Drug: An Overview from a Medicinal Chemistry Point of View
Current Organic Chemistry Meet Our Editorial Board Member
Current Respiratory Medicine Reviews Efficacy of a New Selective Steroid (GW870086) in Asthma: An Adaptive, Randomised, Controlled Trial
Current Drug Therapy COVID-19 Treatment Success After Repeat Courses of Azithromycin: A Report of Three Cases
Infectious Disorders - Drug Targets Rhinitis and Asthma in Children: Comorbitity or United Airway Disease?
Current Pediatric Reviews Antisense Technology: A Selective Tool for Gene Expression Regulation and Gene Targeting
Current Pharmaceutical Biotechnology Potential Role of IL-18 in the Immunopathogenesis of AIDS, HIVAssociated Lipodystrophy and Related Clinical Conditions
Current HIV Research Curcumin Therapeutic Modulation of the Wnt Signaling Pathway
Current Pharmaceutical Biotechnology Emerging Role of Interleukins for the Assessment and Treatment of Liver Diseases
Endocrine, Metabolic & Immune Disorders - Drug Targets Novel Therapeutic Potential of Mitogen-Activated Protein Kinase Activated Protein Kinase 2 (MK2) in Chronic Airway Inflammatory Disorders
Current Drug Targets Multiple Roles of Transient Receptor Potential (TRP) Channels in Inflammatory Conditions and Current Status of Drug Development
Current Topics in Medicinal Chemistry Drug Therapies in the Secondary Prevention of Cardiovascular Diseases:Successes, Shortcomings and Future Directions
Current Vascular Pharmacology Cannabinoids and Neuropathic Pain
Mini-Reviews in Medicinal Chemistry Understanding Membrane Protein Drug Targets in Computational Perspective
Current Drug Targets