A novel prodrug strategy for beta-dicarbonyl carbon acids: syntheses and evaluation of the physicochemical characteristics of C-phosphoryloxymethyl (POM) and phosphoryloxymethyloxymethyl (POMOM) prodrug derivatives.

The C-phosphoryloxymethyl (POM) and phosphoryloxymethyloxymethyl (POMOM) prodrugs resulting from derivatization at the reactive alpha-carbon of beta-dicarbonyl carbon acid drugs represent a unique approach for improving their chemical stability and aqueous solubility. This work evaluates the physicochemical and in vitro enzymatic bioconversion lability of selected prodrugs of phenylbutazone and phenindione. The POM and POMOM prodrug derivatives of phenylbutazone are highly water soluble (>or=250 mg/mL), chemically stable with projected shelf-lives of 4.5 years (pH 3.5, 25 degrees C) and 1.1 years (pH 6.0, 25 degrees C), respectively. Interestingly, both prodrug derivatives do not display a pH-dependency typical of many phosphate monoesters, although the similarities of their apparent thermodynamic activation parameters indicate a hydrolysis mechanism similar to other phosphates. These prodrugs undergo alkaline phosphatases catalyzed bioconversion to their respective carbon acids with an expected faster rate exhibited by the POMOM derivatives. Additionally, in marked contrast to the oxidative instability of phenindione, its POM prodrug is stable. The results from these studies reaffirm the rationale of transiently "masking" the reactive alpha-carbon/proton bond by covalently incorporating a POM or POMOM promoiety. This prodrug strategy presents a twofold advantage, enhancement of aqueous solubility and prevention of oxidative instability, two intrinsic formulation limitations found for beta-dicarbonyl carbon acid drugs. (c) 2009 Wiley-Liss, Inc. and the American Pharmacists Association