Kinetics of degradation in aqueous solution of Abbott-79175, a potent second generation 5-lipoxygenase inhibitor

Abstract

The degradation kinetics of Abbott-79175 in aqueous solution have been studied as a function of pH. Concentration/time plots indicated a pseudo-first order nature of reactions throughout the pH range studied. Additionally, the effects of temperature, ionic strength, and buffer concentration have been examined. From multiple temperature experiments, Arrhenius and activation parameters were calculated. Furthermore, it was determined that upon ionization, Abbott-79175 degradation proceeded independently of ionic strength. These data in addition to the plateau-like nature of the pH-rate constant profile above pH 10 suggest a lack of participation of hydroxide ion during the reaction. This behavior in the neutral and alkaline regions was qualitatively very similar to that of zileuton, a 5-lipoxygenase inhibitor in phase III clinical trials. In addition to allowing the determination of the buffer independent rate constants, kinetic studies as a function of buffer concentration allowed in some of the systems the deduction of which buffer species were catalytic. A multi-parameter model was fitted to the pH buffer independent rate constant data using non-linear regression. This modeling yielded parameters such as the microscopic rate constants and the p K a under the aforementioned conditions. From the pH-rate constant profile, Abbott-79175 was found to be more labile than zileuton throughout the pH range studied. This difference was greater than three orders of magnitude at pH 1. Such acid lability produced a pH profile which had a much narrower region of maximum stability.