The identification and optimization of orally efficacious, small molecule VLA-4 antagonists.
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.
Huryn
Donna M
DM
Wyeth Research, Princeton, NJ 08543, USA. hurynd@wyeth.com
Konradi
Andrei W
AW
Ashwell
Susan
S
Freedman
Stephen B
SB
Lombardo
Louis J
LJ
Pleiss
Michael A
MA
Thorsett
Eugene D
ED
Yednock
Ted
T
Kennedy
Jeffrey D
JD
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
D004151:Dipeptides; D039041:Integrin alpha4beta1