In vivo characterization of a novel γ -secretase inhibitor SCH 697466 in rodents and investigation of strategies for managing notch-related side effects

Abstract

Substantial evidence implicates β -amyloid (A β) peptides in the etiology of Alzheimer's disease (AD). A β is produced by the proteolytic cleavage of the amyloid precursor protein by β - and γ -secretase suggesting that γ -secretase inhibition may provide therapeutic benefit for AD. Although many γ -secretase inhibitors have been shown to be potent at lowering A β, some have also been shown to have side effects following repeated administration. All of these side effects can be attributed to altered Notch signaling, another γ -secretase substrate. Here we describe the in vivo characterization of the novel γ -secretase inhibitor SCH 697466 in rodents. Although SCH 697466 was effective at lowering A β, Notch-related side effects in the intestine and thymus were observed following subchronic administration at doses that provided sustained and complete lowering of A β. However, additional studies revealed that both partial but sustained lowering of A β and complete but less sustained lowering of A β were successful approaches for managing Notch-related side effects. Further, changes in several Notch-related biomarkers paralleled the side effect observations. Taken together, these studies demonstrated that, by carefully varying the extent and duration of A β lowering by γ -secretase inhibitors, it is possible to obtain robust and sustained lowering of A β without evidence of Notch-related side effects. © 2013 Lynn A. Hyde et al.