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 and 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical with the HMG-CoA reductase inhibitors lovastatin, simvastatin, and statins I-IV were measured. This series of diene-containing drugs is known to be prone to oxidation. The tert-butoxyl radical was generated by the thermolysis of di-tert-butylperoxyoxalate at 40 degrees C. 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 experimentally determined product ratios of t-butanol to acetone and the known rate of beta-scission of tert-butoxyl radical. The rate constants for the reaction with DPPH radical were measured spectrophotometrically by monitoring the loss of DPPH radical as a function of substrate concentration. The rate constants correlate well with the structure of the molecules studied. These kinetic techniques allow for oxidatively sensitive compounds to be identified early in the drug development cycle. The tert-butoxyl radical, a strong hydrogen atom abstractor, is representative of the hydroxyl (. OH) and alkoxyl (. OR) radicals; in contrast the DPPH radical, a much weaker radical, is a good kinetic model for hydroperoxyl (. OOH) and peroxyl (. OOR) radicals. These kinetic methods can be used to quantitatively assess the lability of drug candidates towards reaction with oxygen-centered radicals at an early stage of development and facilitate the design of inhibiting strategies.
Karki
S B
SB
Pharmaceutical Research and Development Department, Merck Research Laboratories, West Point, Pennsylvania 19486, USA. shyam_karki@merck.com
Treemaneekarn
V
V
Kaufman
M J
MJ
D015764:Bepridil / Q000031:analogs & derivatives* / Q000737:chemistry; D001713:Biphenyl Compounds; D000440:Butanols / Q000737:chemistry*; D005609:Free Radicals; D006834:Hydrazines / Q000737:chemistry*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000737:chemistry*; D007700:Kinetics; D008148:Lovastatin / Q000737:chemistry; D008968:Molecular Conformation; D010084:Oxidation-Reduction; D010851:Picrates; D019821:Simvastatin / Q000737:chemistry; D013696:Temperature
D001713:Biphenyl Compounds; D000440:Butanols; D005609:Free Radicals; D006834:Hydrazines; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D010851:Picrates; D015764:Bepridil; D008148:Lovastatin; D019821:Simvastatin; C004931:1,1-diphenyl-2-picrylhydrazyl