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 e aters of etidronic acid as eridronate prodrugs is reported. Tetramethyl est er 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 o f 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 hydrol ysed and the parent drug was released. This finding was successfully applie d in the design of tetrapivaloyloxymethyl ester of acetylated etidronic aci d which released etidronic acid via enzymatic (first step) and chemical (se cond step) hydrolysis in liver homogenate. However, the corresponding tri-s ubstituted pivaloyloxymethyl ester having adequate water-solubility and lip ophilicity (log P-app 0.6 at pH 7.4), is probably the most potential prodru g candidate reported to enhance the oral bioavailability of etidronate. (C) 2000 Elsevier Science B.V. All rights reserved.