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:Wyeth Research, CN8000,Princeton, NJ 08543, USA.
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.
