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International Journal of Alzheimer’s Disease
Volume 2013 (2013), Article ID 823528, 14 pages
http://dx.doi.org/10.1155/2013/823528
Research Article

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

1Department of Neuroscience, Merck Research Laboratories, Kenilworth, NJ 07033, USA
2Department of Molecular Biomarkers, Merck Research Laboratories, Kenilworth, NJ 07033, USA
3Department of Medicinal Chemistry, Merck Research Laboratories, Kenilworth, NJ 07033, USA
4Department of Drug Metabolism and Pharmoackinetics, Merck Research Laboratories, Kenilworth, NJ 07033, USA

Received 29 August 2012; Accepted 27 November 2012

Academic Editor: Jeremy Toyn

Copyright © 2013 Lynn A. Hyde et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Substantial evidence implicates -amyloid (A ) peptides in the etiology of Alzheimer’s disease (AD). A is produced by the proteolytic cleavage of the amyloid precursor protein by - and -secretase suggesting that -secretase inhibition may provide therapeutic benefit for AD. Although many -secretase inhibitors have been shown to be potent at lowering A , 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 -secretase substrate. Here we describe the in vivo characterization of the novel -secretase inhibitor SCH 697466 in rodents. Although SCH 697466 was effective at lowering A , Notch-related side effects in the intestine and thymus were observed following subchronic administration at doses that provided sustained and complete lowering of A . However, additional studies revealed that both partial but sustained lowering of A and complete but less sustained lowering of A 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 lowering by -secretase inhibitors, it is possible to obtain robust and sustained lowering of A without evidence of Notch-related side effects.