In Vivo Characterization of a Novel -Secretase Inhibitor SCH 697466 in Rodents and Investigation of Strategies for Managing Notch-Related Side Effects
Aβ40 levels expressed as a percent of vehicle in (a) plasma and (b) cortex, (c) thymus weight, and (d) percent area in the ileum covered by PAS stain following 11 days of q.d. administration (left side of graphs) or 6 days of b.i.d. administration (right side of graphs) of SCH 697466 in nontransgenic B6C3F1 mice. The final dose of SCH 697466 was given 3 hr prior to tissue harvesting. Representative examples of the PAS stained ileum from (e) 11 day q.d. vehicle-treated mouse; 13% PAS staining, (f) 11 day q.d. 100 mg/kg SCH 697466 treated mouse; 16% PAS staining, (g) 6 day b.i.d. vehicle-treated mouse; 11% PAS staining, and (h) 6 day b.i.d. 100 mg/kg SCH 697466 treated mouse; 39% PAS staining. Increased PAS staining was only observed in the 6 day b.i.d. 100 mg/kg treated group. versus vehicle, Dunnett post hoc test.