Aryl ester prodrugs of cyclic HPMPC. I: PhysicochemicaI characterization and in vitro biological stability

Purpose. The chemical, enzymatic, and biological stabilities and physical p roperties of a series of salicylate and aryl eater prodrugs of the antivira l agent, cyclic HPMPC, were evaluated to support the selection of a lead co mpound for clinical development. Methods. Chemical stabilities of the prodrugs in buffered solutions at 37 d egrees C were determined. Stability was also studied in the presence of por cine liver carboxyesterases (PLCE) at pH 7.4 and 25 degrees C. Tissue stabi lities were examined in both human and dog intestinal homogenates, plasmas and liver homogenates. Prodrug and product concentrations were determined b y reverse phase HPLC. Results. Chemical degradation of the prodrugs resulted in the formation of both cyclic HPMPC and the corresponding HPMPC monoester. Chemical stability was dependent on the orientation of the exo-cyclic ligand; the equatorial isomers were 5.4- to 9.4-fold more reactive than the axial isomers. In the presence of PLCE, the salicylate prodrugs cleaved exclusively to give cycli c HPMPC and not the HPMPC monoester. In plasma, but not intestinal or liver homogenates, the salicylate esters of cyclic HPMPC cleaved readily with a rate dependent on the chain length of the alkyl ester substituent. Conclusions. The carboxylate function on the salicylate prodrugs of cyclic HPMPC provides an additional handle to chemically modify the lipophilicity, solubility and the biological reactivity of the prodrug. In tissue and enz ymatic studies, the major degradation product is cyclic HPMPC. The salicyla te ester prodrugs are attractive drug candidates for further in vivo evalua tion.