Synthesis and in-vitro/in-vivo evaluation of orally administered entacapone prodrugs

Entacapone is a new inhibitor of catechol-O-methyltransferase (COMT) that i s used as an adjunct to L-dopa therapy in the treatment of Parkinson's dise ase. The bioavailability of orally administered entacapone is, however, rel atively low (29-46 %). In this study we have prepared more lipophilic acyl and acyloxyacyl esters, an acyloxy alkyl ether and an alkyloxycarbonyl este r of entacapone, and we have evaluated them as potential prodrugs to enhanc e the oral bioavailability of entacapone. All the derivatives fulfilled pro drug criteria and released entacapone in human serum in-vitro. The oral bio availability of monopivaloyl (1a) and dipivaloyl (1b) esters of entacapone were investigated further in rats. The lipophilicity of lb was high (log P- app 4.0 at pH 7.4) but its oral bioavailability was low (F = 0.6 %), most p robably due to its low aqueous solubility. The monopivaloyl ester of entaca pone (1a) had a higher lipophilicity (log P-app 0.80) than entacapone (log P-app 0.18) at pH 7.4 while maintaining an aqueous solubility equal to enta capone. However, oral bioavailability was not increased when compared with the parent drug entacapone (F = 7.0 % and 10.4 %, respectively).