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.
Rautio
Jarkko
J
University of Eastern Finland, School of Pharmacy, FI-70211 Kuopio, Finland. Jarkko.Rautio@uku.fi
Leppänen
Jukka
J
Lehtonen
Marko
M
Laine
Krista
K
Koskinen
Mikko
M
Pystynen
Jarmo
J
Savolainen
Jouko
J
Sairanen
Mikko
M
D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D065098:Catechol O-Methyltransferase Inhibitors; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D008297:Male; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar
D065098:Catechol O-Methyltransferase Inhibitors; D004791:Enzyme Inhibitors; D011355:Prodrugs