Synthesis, characterization and evaluation of pro-drugs of VLA-4 antagonists.
A pro-drug strategy to identify orally efficacious VLA-4 antagonists is described. Potential pro-drugs were evaluated for their physical chemical characteristics and in vitro properties, including solubility, stability, permeability and plasma stability. Based on this characterization, promising compounds were identified for in vivo pharmacokinetic evaluation. These studies resulted in the identification of a pro-drug that exhibited desirable blood levels in PK studies in several different species.
Huryn
Donna M
DM
Chemical & Screening Sciences, Wyeth Research, CN 8000, Princeton, NJ 08543, USA. hurynd@wyeth.com
Ashwell
Susan
S
Baudy
Reinhardt
R
Dressen
Darren B
DB
Gallaway
William
W
Grant
Francine S
FS
Konradi
Andrei
A
Ley
Robert W
RW
Petusky
Susan
S
Pleiss
Michael A
MA
Sarantakis
Dimitri
D
Semko
Christopher M
CM
Sherman
Mary M
MM
Tio
Cesar
C
Zhang
Lu
L
D000818:Animals; D004353:Drug Evaluation, Preclinical / Q000379:methods; D039041:Integrin alpha4beta1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008297:Male; D011355:Prodrugs / Q000138:chemical synthesis* / Q000378:metabolism; D051381:Rats
D039041:Integrin alpha4beta1; D011355:Prodrugs