KINETICS OF DEGRADATION IN AQUEOUS-SOLUTION OF ABBOTT-79175, A POTENT2ND GENERATION 5-LIPOXYGENASE INHIBITOR

The degradation kinetics of Abbott-79175 in aqueous solution have been studied as a function of pH. Concentration/time plots indicated a pse udo-first order nature of reactions throughout the pH range studied. A dditionally, the effects of temperature, ionic strength, and buffer co ncentration have been examined. From multiple temperature experiments, Arrhenius and activation parameters were calculated. Furthermore, it was determined that upon ionization, Abbott-79175 degradation proceede d independently of ionic strength. These data in addition to the plate au-like nature of the pH-rate constant profile above pH 10 suggest a l ack of participation of hydroxide ion during the reaction. This behavi or 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 indepe ndent rate constants, kinetic studies as a function of buffer concentr ation allowed in some of the systems the deduction of which buffer spe cies were catalytic. A multi-parameter model was fitted to the pH buff er independent rate constant data using non-linear regression. This mo deling yielded parameters such as the microscopic rate constants and t he pK(a) under the aforementioned conditions. From the pH-rate constan t profile, Abbott-79175 was found to be more labile than zileuton thro ughout the pH range studied. This difference was greater than three or ders of magnitude at pH 1. Such acid lability produced a pH profile wh ich had a much narrower region of maximum stability.