Oxidation of HMG-CoA reductase inhibitors by tert-butoxyl and 1,1-diphenyl-2-picrylhydrazyl radicals: Model reactions for predicting oxidatively sensitive compounds during preformulation

Hydrogen atom abstraction rate constants for the reaction of tert-butoxyl a nd 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical with the HMG-CoA reductase inhibitors lovastatin, simvastatin, and statins I-IV were measured. This se ries of diene-containing drugs is known to be prone to oxidation. The tert- butoxyl radical was generated by the thermolysis of di-tert-butylperoxyoxal ate at 40 degreesC. A competitive kinetic method was used to determine the relative rate of hydrogen atom abstraction by tert-butoxyl radical to beta -scission. The absolute rate constants were calculated using the experiment ally determined product ratios of t-butanol to acetone and the known rate o f beta -scission of tert-butoxyl radical. The rate constants for the reacti on with DPPN: radical were measured spectrophotometrically by monitoring th e loss of DPPH radical as a function of substrate concentration. The rate c onstants correlate well with the structure of the molecules studied. These kinetic techniques allow for oxidatively sensitive compounds to be identifi ed early in the drug development cycle. The tert-butoxyl radical, a strong hydrogen atom abstractor, is representative of the hydroxyl ( . OH) and alk oxyl ( . OR) radicals; in contrast the DPPH radical, a much weaker radical, is a good kinetic model for hydroperoxyl ( . OOH) and peroxyl ( . OOR) rad icals. These kinetic methods can be used to quantitatively assess the labil ity of drug candidates towards reaction with oxygen-centered radicals at an early stage of development and facilitate the design of inhibiting strateg ies. (C) 2000 Wiley-Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 89:1518-1524, 2000.