title: The identification and optimization of orally efficacious, small molecule VLA-4 antagonists.
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.
authors.affiliation: Wyeth Research, Princeton, NJ 08543, USA. hurynd@wyeth.com
authors.forename: Donna M
authors.initials: DM
authors.lastname: Huryn
authors.forename: Andrei W
authors.initials: AW
authors.lastname: Konradi
authors.forename: Susan
authors.initials: S
authors.lastname: Ashwell
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Freedman
authors.forename: Louis J
authors.initials: LJ
authors.lastname: Lombardo
authors.forename: Michael A
authors.initials: MA
authors.lastname: Pleiss
authors.forename: Eugene D
authors.initials: ED
authors.lastname: Thorsett
authors.forename: Ted
authors.initials: T
authors.lastname: Yednock
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Kennedy
mesh_terms: D000818:Animals; D001249:Asthma / Q000188:drug therapy; D002448:Cell Adhesion / Q000187:drug effects; D004151:Dipeptides / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D006801:Humans; D039041:Integrin alpha4beta1 / Q000037:antagonists & inhibitors*; D009103:Multiple Sclerosis / Q000188:drug therapy; D013329:Structure-Activity Relationship
chemical_list: D004151:Dipeptides; D039041:Integrin alpha4beta1