Bisphosphonate prodrugs: synthesis and in vitro evaluation of alkyl and acyloxymethyl esters of etidronic acid as bioreversible prodrugs of etidronate.
The synthesis and preliminary evaluation of novel alkyl and acyloxymethyl esters of etidronic acid as etidronate prodrugs is reported. Tetramethyl ester of etidronic acid was found be isomerized at pH 7.4 and P-C-P bridge was rearranged to P-C-O-P. This unwanted process was prevented via acylation of the bridging carbon's alcohol group. Acylation showed to be stable if one or more phosphonic OH- groups were substituted. However, when none of the phosphonic OH- groups were substituted, the acylation was chemically hydrolysed and the parent drug was released. This finding was successfully applied in the design of tetrapivaloyloxymethyl ester of acetylated etidronic acid which released etidronic acid via enzymatic (first step) and chemical (second step) hydrolysis in liver homogenate. However, the corresponding tri-substituted pivaloyloxymethyl ester having adequate water-solubility and lipophilicity (logP(app) 0.6 at pH 7.4), is probably the most potential prodrug candidate reported to enhance the oral bioavailability of etidronate.
Department of Pharmaceutical Chemistry, University of Kuopio, P.O. Box 1627, FIN-70211, Kuopio, Finland.
R
R
Niemi
P
P
Turhanen
J
J
Vepsäläinen
H
H
Taipale
T
T
Järvinen
D000818:Animals; D004164:Diphosphonates / Q000097:blood / Q000138:chemical synthesis / Q000493:pharmacokinetics; D012968:Etidronic Acid / Q000097:blood / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D006801:Humans; D008099:Liver / Q000378:metabolism; D011355:Prodrugs / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D011817:Rabbits
D004164:Diphosphonates; D011355:Prodrugs; D012968:Etidronic Acid