BMS-708163 (Avagacestat) is a potent, selective γ-secretase inhibitor of Aβ40 and Aβ42 with IC50 of 0.3 nM and 0.27 nM, respectively. BMS-708163 binds directly to the presenilin-1 N-terminal fragment and that binding can be challenged by other pan-GSIs, but not by γ-secretase modulators. BMS-708163 blocks the binding of four different active site-directed GSI photoaffinity probes. Administration of a single dose of 200 or 400 mg of BMS-708163 resulted in a marked decrease in CSF Aβ(1-38), Aβ(1-40) and Aβ(1-42) concentrations vs placebo; with smaller decreases observed in the 50 mg dose group. BMS-708163 (Avagacestat) was quickly absorbed into the systemic circulation, with a mean time to reach maximum plasma concentration (t(max)) of approximately 1-2 h, and a CSF t(max) of approximately 3 h. BMS-708163 is 190-fold more selective for APP than Notch, having an IC50 of 58 nM for Notch.
| Cell Experiment | |
|---|---|
| Cell lines | |
| Preparation method | |
| Concentrations | |
| Incubation time | |
| Animal Experiment | |
|---|---|
| Animal models | Harlan Sprague Dawley rat or ATM-405-142K9 naive II dog |
| Formulation | 99% PEG-400, 1% Tween-80 (rat)，or 94% labrafil-1944, 5% ethanol, 1% Tween-80 (dog) |
| Dosages | 10 mg/kg (rat) or 2.5 mg/kg (dog) |
| Administration | oral gavage |
| Molecular Weight | 520.88 |
| Formula | C20H17ClF4N4O4S |
| CAS Number | 1146699-66-2 |
| Solubility (25°C) | DMSO 100 mg/mL |
| Storage |
Powder -20°C 3 years ; 4°C 2 years In solvent -80°C 6 months ; -20°C 1 month |
| Species | Mouse | Rat | Rabbit | Guinea pig | Hamster | Dog |
| Weight (kg) | 0.02 | 0.15 | 1.8 | 0.4 | 0.08 | 10 |
| Body Surface Area (m2) | 0.007 | 0.025 | 0.15 | 0.05 | 0.02 | 0.5 |
| Km factor | 3 | 6 | 12 | 8 | 5 | 20 |
| Animal A (mg/kg) = Animal B (mg/kg) multiplied by | Animal B Km |
| Animal A Km |
For example, to modify the dose of Compound A used for a mouse (20 mg/kg) to a dose based on the BSA for a rat, multiply 20 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for Compound A of 10 mg/kg.
[3] Crump CJ, et al. Biochemistry. BMS-708,163 targets presenilin and lacks notch-sparing activity.
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