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Published on: October 11, 2013
The identification and optimization of orally efficacious, small molecule VLA-4 antagonists
Donna M Huryn1, Andrei W Konradi, Susan Ashwell
1Wyeth Research, Princeton, NJ 08543, USA. hurynd@wyeth.com
Abstract:
The identification of orally active, small molecule antagonists of the alpha4beta1 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 alpha4 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.
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