ABSTRACT
In our investigations to synthesize inhibitors of smooth muscle cell (SMC) proliferation, compound 6a displayed submicromolar activity in in vitro antiproliferative assays and reduced intimal thickening using a rat balloon angioplasty model via i.v. administration. In order to identify analogs that could be administered orally, the chemical instability of the C-4',6' acetal of compound 6a was addressed. Several novel variants with increased acid stability and comparable in vitro activity were prepared.
Subject(s)
Maltose/pharmacology , Muscle, Smooth, Vascular/drug effects , Angioplasty, Balloon/adverse effects , Animals , Benzyl Compounds/chemical synthesis , Benzyl Compounds/pharmacology , Cell Proliferation/drug effects , Drug Stability , Hydrogen-Ion Concentration , Male , Maltose/chemical synthesis , Models, Animal , Muscle, Smooth, Vascular/injuries , Muscle, Smooth, Vascular/pathology , Rats , Rats, Sprague-Dawley , Structure-Activity RelationshipABSTRACT
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.
