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

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.

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