Synthesis of a water-soluble prodrug of entacapone.
Entacapone was reacted with phosphorous oxychloride in dry pyridine to yield a phosphate ester. The phosphate promoiety increased aqueous solubility of the parent drug by more than 1700- and 20-fold at pH 1.2 and 7.4, respectively. The phosphate ester provides adequate stability (t(1/2) = 2227 h; pH 7.4) towards chemical hydrolysis, and allowed for release of the parent drug via enzymatic hydrolysis in liver homogenate.
Leppänen
J
J
Department of Pharmaceutical Chemistry, University of Kuopio, Finland. jukka.leppanen@uku.fi
Huuskonen
J
J
Savolainen
J
J
Nevalainen
T
T
Taipale
H
H
Vepsäläinen
J
J
Gynther
J
J
Järvinen
T
T
D065098:Catechol O-Methyltransferase Inhibitors; D002396:Catechols / Q000138:chemical synthesis*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis*; D006863:Hydrogen-Ion Concentration; D009570:Nitriles; D011355:Prodrugs / Q000138:chemical synthesis*; D012995:Solubility
D065098:Catechol O-Methyltransferase Inhibitors; D002396:Catechols; D004791:Enzyme Inhibitors; D009570:Nitriles; D011355:Prodrugs; C071192:entacapone