Design, synthesis and in vitro/in vivo evaluation of orally bioavailable prodrugs of a catechol- O-methyltransferase inhibitor

Compound 1 is an investigational, nanomolar inhibitor of catechol- O-methyltransferase (COMT) that suffers from poor oral bioavailability, most probably due to its low lipophilicity throughout most of the gastrointestinal tract and, to a lesser extent, its rapid systemic clearance. Several lipophilic esters were designed as prodrugs and synthesized in an attempt to optimize presystemic drug absorption. A modest twofold increase in 6-h exposure of 1 was observed with two prodrugs, compared to that of 1, after oral treatment in rats.