title: Synthesis, characterization and evaluation of pro-drugs of VLA-4 antagonists.
abstract: 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.
authors.affiliation: Chemical & Screening Sciences, Wyeth Research, CN 8000, Princeton, NJ 08543, USA. hurynd@wyeth.com
authors.forename: Donna M
authors.initials: DM
authors.lastname: Huryn
authors.forename: Susan
authors.initials: S
authors.lastname: Ashwell
authors.forename: Reinhardt
authors.initials: R
authors.lastname: Baudy
authors.forename: Darren B
authors.initials: DB
authors.lastname: Dressen
authors.forename: William
authors.initials: W
authors.lastname: Gallaway
authors.forename: Francine S
authors.initials: FS
authors.lastname: Grant
authors.forename: Andrei
authors.initials: A
authors.lastname: Konradi
authors.forename: Robert W
authors.initials: RW
authors.lastname: Ley
authors.forename: Susan
authors.initials: S
authors.lastname: Petusky
authors.forename: Michael A
authors.initials: MA
authors.lastname: Pleiss
authors.forename: Dimitri
authors.initials: D
authors.lastname: Sarantakis
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Semko
authors.forename: Mary M
authors.initials: MM
authors.lastname: Sherman
authors.forename: Cesar
authors.initials: C
authors.lastname: Tio
authors.forename: Lu
authors.initials: L
authors.lastname: Zhang
mesh_terms: 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
chemical_list: D039041:Integrin alpha4beta1; D011355:Prodrugs