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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.

In Vivo Characterization of a Novel -Secretase Inhibitor SCH 697466 in Rodents and Investigation of Strategies for Managing Notch-Related Side Effects