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Current Topics in Medicinal Chemistry


ISSN (Print): 1568-0266
ISSN (Online): 1873-4294

The Identification and Optimization of Orally Efficacious, Small Molecule VLA-4 Antagonists

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

Volume 4 , Issue 14 , 2004

Page: [1473 - 1484] Pages: 12

DOI: 10.2174/1568026043387467

Price: $65


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

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