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NEUROPHARMACOLOGY
in Vivo and in Vitro Using the 
-Secretase Inhibitor, LY-450139
CNS Discovery, Pfizer, Inc., Groton, Connecticut
LY-450139 is a 
-secretase inhibitor shown to have efficacy in multiple cellular and animal models. Paradoxically, robust elevations of plasma amyloid-
(A) have been reported in dogs and humans after administration of subefficacious doses. The present study sought to further evaluate A responses to LY-450139 in the guinea pig, a nontransgenic model that has an A sequence identical to that of human. Male guinea pigs were treated with LY-450139 (0.2–60 mg/kg), and brain, cerebrospinal fluid, and plasma A levels were characterized at 1, 3, 6, 9, and 14 h postdose. Low doses significantly elevated plasma A levels at early time points, with return to baseline within hours. Higher doses inhibited A levels in all compartments at early time points, but elevated plasma A levels at later time points. To determine whether this phenomenon occurs under steady-state drug exposure, guinea pigs were implanted with subcutaneous minipumps delivering LY-450139 (0.3–30 mg/kg/day) for 5 days. Plasma A was significantly inhibited at 10–30 mg/kg/day, but significantly elevated at 1 mg/kg/day. To further understand the mechanism of A elevation by LY-450139, H4 cells overexpressing the Swedish mutant of amyloid-precursor protein and a mouse embryonic stem cell-derived neuronal cell line were studied. In both cellular models, elevated levels of secreted A were observed at subefficacious concentrations, whereas dose-responsive inhibition was observed at higher concentrations. These results suggest that LY-450139 modulates the -secretase complex, eliciting A lowering at high concentrations but A elevation at low concentrations.
Address correspondence to: Dr. Thomas A. Lanz, Pfizer, Inc., Eastern Point Rd., MS# 8220-4183, Groton, CT 06340. E-mail: thomas.a.lanz{at}pfizer.com
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