Bisphosphonate prodrugs: Synthesis and in vitro evaluation of novel acyloxyalkyl esters of clodronic acid

Novel tetra-, tri-, and P,P'-dipivaloyloxymethyl esters of clodronic acid w ere synthesized, and their properties as possible prodrugs of clodronate we re evaluated in vitro. All pivaloyloxymethyl esters were significantly more lipophilic (log P-app ranged from -2.1 to 7.4) than clodronate (log P-app less than or equal to -5.4), which suggests that it may be possible to chan ge the intestinal absorption mechanism of clodronate from a paracellular to a transcellular pathway by a prodrug approach. Pivaloyloxymethyl eaters de graded rapidly in 10% rabbit liver homogenate, and half-lives of tri- and P ,P'-diesters were 1.1 and 14 min, respectively. The intermediate degradatio n products were further degraded, and clodronic acid was released in quanti tative amounts. In human serum, the stability of pivaloyloxymethyl esters w as comparable to their stability in phosphate buffer (pH 7.4), which sugges ts that their degradation in human serum is mostly due to the chemical hydr olysis. Benzoyloxypropyl esters of clodronic acid were also synthesized, bu t they did not release clodronic acid due to the enzymatic and chemical sta bility of the formed S-hydroxypropyl phosphonate esters and are, therefore, not prodrugs.