title: Synthesis and in-vitro/in-vivo evaluation of orally administered entacapone prodrugs.
abstract: Entacapone is a new inhibitor of catechol-O-methyltransferase (COMT) that is used as an adjunct to L-dopa therapy in the treatment of Parkinson's disease. The bioavailability of orally administered entacapone is, however, relatively low (29-46%). In this study we have prepared more lipophilic acyl and acyloxyacyl esters, an acyloxy alkyl ether and an alkyloxycarbonyl ester of entacapone, and we have evaluated them as potential prodrugs to enhance the oral bioavailability of entacapone. All the derivatives fulfilled prodrug criteria and released entacapone in human serum in-vitro. The oral bioavailability of monopivaloyl (1a) and dipivaloyl (1b) esters of entacapone were investigated further in rats. The lipophilicity of 1b was high (log Papp 4.0 at pH 7.4) but its oral bioavailability was low (F = 0.6%), most probably due to its low aqueous solubility. The monopivaloyl ester of entacapone (1a) had a higher lipophilicity (log Papp 0.80) than entacapone (log Papp 0.18) at pH 7.4 while maintaining an aqueous solubility equal to entacapone. However, oral bioavailability was not increased when compared with the parent drug entacapone (F = 7.0% and 10.4%, respectively).
authors.affiliation: Department of Pharmaceutical Chemistry, University of Kuopio, Finland. jukka.leppanen@uku.fi
authors.forename: J
authors.initials: J
authors.lastname: Leppänen
authors.forename: J
authors.initials: J
authors.lastname: Savolainen
authors.forename: T
authors.initials: T
authors.lastname: Nevalainen
authors.forename: M
authors.initials: M
authors.lastname: Forsberg
authors.forename: J
authors.initials: J
authors.lastname: Huuskonen
authors.forename: H
authors.initials: H
authors.lastname: Taipale
authors.forename: J
authors.initials: J
authors.lastname: Gynther
authors.forename: P T
authors.initials: PT
authors.lastname: Männistö
authors.forename: T
authors.initials: T
authors.lastname: Järvinen
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000978:Antiparkinson Agents / Q000097:blood / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D001682:Biological Availability; D002396:Catechols / Q000097:blood / Q000138:chemical synthesis* / Q000493:pharmacokinetics*; D004952:Esters / Q000138:chemical synthesis / Q000493:pharmacokinetics; D004987:Ethers / Q000138:chemical synthesis / Q000493:pharmacokinetics; D006207:Half-Life; D006801:Humans; D006868:Hydrolysis / Q000187:drug effects; D008297:Male; D008563:Membrane Lipids / Q000378:metabolism; D009570:Nitriles; D011355:Prodrugs / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D051381:Rats; D017208:Rats, Wistar; D012995:Solubility; D014867:Water
chemical_list: C451245:2-cyano-N,N-diethyl-3-(3,4-dipivaloyloxy-5-nitrophenyl)propenamide; D000978:Antiparkinson Agents; D002396:Catechols; D004952:Esters; D004987:Ethers; D008563:Membrane Lipids; D009570:Nitriles; D011355:Prodrugs; D014867:Water; C071192:entacapone