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

J Med Chem. 1999 Dec 2;42(24):5053-8. doi: 10.1021/jm991109o.

Abstract

Novel tetra-, tri-, and P,P'-dipivaloyloxymethyl esters of clodronic acid were synthesized, and their properties as possible prodrugs of clodronate were 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) < or = -5.4), which suggests that it may be possible to change the intestinal absorption mechanism of clodronate from a paracellular to a transcellular pathway by a prodrug approach. Pivaloyloxymethyl esters degraded rapidly in 10% rabbit liver homogenate, and half-lives of tri- and P,P'-diesters were 1.1 and 14 min, respectively. The intermediate degradation products were further degraded, and clodronic acid was released in quantitative amounts. In human serum, the stability of pivaloyloxymethyl esters was comparable to their stability in phosphate buffer (pH 7.4), which suggests that their degradation in human serum is mostly due to the chemical hydrolysis. Benzoyloxypropyl esters of clodronic acid were also synthesized, but they did not release clodronic acid due to the enzymatic and chemical stability of the formed 3-hydroxypropyl phosphonate esters and are, therefore, not prodrugs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Benzoates / chemistry
  • Benzoates / metabolism
  • Biological Availability
  • Blood / metabolism
  • Carboxylesterase
  • Carboxylic Ester Hydrolases / metabolism
  • Chemical Phenomena
  • Chemistry, Physical
  • Clodronic Acid / chemistry*
  • Clodronic Acid / metabolism
  • Clodronic Acid / pharmacokinetics
  • Diphosphonates / chemical synthesis*
  • Diphosphonates / metabolism
  • Drug Stability
  • Half-Life
  • Humans
  • Hydrogen-Ion Concentration
  • Hydrolysis
  • Intestinal Absorption
  • Liver / metabolism
  • Phosphodiesterase I
  • Phosphoric Diester Hydrolases / metabolism
  • Prodrugs / chemical synthesis*
  • Prodrugs / metabolism
  • Rabbits
  • Solutions
  • Structure-Activity Relationship

Substances

  • Benzoates
  • Diphosphonates
  • Prodrugs
  • Solutions
  • tetra(pivaloyloxymethyl) (dichloromethylene)bisphosphonate
  • Clodronic Acid
  • Carboxylic Ester Hydrolases
  • Carboxylesterase
  • Phosphoric Diester Hydrolases
  • Phosphodiesterase I