化合物信息

Description

Alzheimer's disease

Description

BMS-708163 is a potent, selective γ-secretase inhibitor of Aβ40 and Aβ42 with IC50 of 0.3 nM and 0.27 nM, respectively.

Targets

IC₅₀

In Vitro

BMS-708163 exhibits weaker selectivity for inhibition of Notch processing with 193-fold IC50 value. ^[1]

In Vivo

Oral administration of BMS-708163 significantly reduces Aβ40 levels for sustained periods in brain, plasma, and cerebrospinal fluid in rats and dogs. BMS-708163 has no dose-limiting effects in dogs (3 mg/kg during 6 months), with a high brain to plasma ratio (2.4). ^[1]

Clinical Trials

Phase II clinical trial in patients with Alzheimer disease has been completed.

Features

BMS-708163 looks to be more “notch sparing” than semagacestat (LY450139).

Inhibition of Aβ formation

BMS-708163 is assayed for Aβ40 or Aβ42 inhibition in cells using H4 APP751 SWE clone 8.20, an H4 neuroglioma cell line stably expressing the Swedish mutant of APP751. Cells are maintained in log phase through twice weekly passage at a 1:20 dilution. For IC50 determinations, 30 μL cells (1.5×10⁴ cells/well) in DMEM media containing 0.0125% BSA are seeded directly into 384-well plates containing 0.1 μL serially diluted BMS-708163 in DMSO. Following incubation for 19 hours in 5% CO₂ at 37 °C, plates are briefly centrifuged (10³ rpm, 5 min). A 10 μL aliquot from each well is transferred to a second assay plate for Aβ40 measurements. Antibody cocktails are freshly prepared by dilution into 40 mM Tris-HCl (pH 7.4) with 0.2% BSA and added to assay plates. For Aβ42 measurements, antibodies specific for the Aβ42 neoepitope (565, developed at Bristol-Myers Squibb; conjugated to the Wallac reagent) and the N-terminal sequence of Aβ peptide (26D6, developed at SIBIA/Bristol-Myers Squibb; conjugated to APC) are mixed and 20 μL of the mixture is added to each well of the incubated cell plate yielding a final concentration of 0.8 ng/well 565 and 75 ng/well 26D6. For the Aβ40 measurements, antibodies specific for the Aβ40 neoepitope (TSD, developed at Bristol-Myers Squibb; conjugated to the Wallac reagent) and 26D6 as described above are mixed and 20 μL of the mixture is added to the 10 μL aliquots which have been removed previously from the cell plate yielding a final concentration of 1.6 ng/well TSD and 17.5 ng/well 26D6. Assay plates containing antibodies are sealed with aluminum foil and incubated overnight at 4 °C. Signal is determined using a Viewlux counter and IC50 values are determined.

Animal Models

Female Harlan Sprague-Dawley rats or ATM-405-142K9 with 7- 10 month old na?ve, grade II beagles

Formulation

99% PEG-400, 1% Tween-80 (rats) or 94% labrafil-1944, 5% ethanol, 1% tween-80 (dogs)

Doses

10 mg/kg (rats) or 2.5 mg/kg (dogs)

Administration

Dosed daily by oral gavage