Synthesis and in vitro/in vivo evaluation of novel oral N-alkyl- and N,N-dialkyl-carbamate esters of entacapone

Entacapone has a relatively low oral bioavailability which may, in part, be due to its low aqueous solubility at low pH and/or its hydrophilic charact er at neutral pH. Various novel N-alkyl and N,N-dialkyl carbamate esters of entacapone were synthesized as possible prodrugs of entacapone in order to increase its aqueous solubility at an acidic pH and to increase its lipoph ilicity at neutral pH. Oral bioavailability of entacapone and selected carb amate esters were investigated in rats. Both N-alkyl and N,N-dialkyl carbam ate esters were relatively stable against chemical hydrolysis at pH 7.4 (t( 1/2) = 14.9-20.7 h), but hydrolyzed rapidly (t(1/2) = 0.8-2.7 h) in human s erum. However, in contrast to N-alkyl carbamates, N,N-dialkyl carbamates di d not release entacapone in in vitro enzymatic hydrolysis (human serum) stu dies. N-Alkyl carbamates, 2a-c, showed increased aqueous solubility at pH 7 .4, of which 2a and 2c also show increased aqueous solubility at pH 5.0, co mpared to entacapone, In addition to increased aqueous solubility, 2c showe d increased lipophilicity at pH 7.4. However, two N-alkyl carbamates of ent acapone did not increase the oral bioavailability of the parent drug in rat s. Thus, it can be concluded that the relatively low lipophilicity of entac apone is not the cause of its low bioavailability. (C) 2000 Elsevier Scienc e Inc. All rights reserved.