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.
|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)|
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 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 resveratrol of 11.2 mg/kg.
|Solubility||DMSO 100 mg/mL|
Discovery and Evaluation of BMS-708163, a Potent, Selective and Orally Bioavailable γ-Secretase Inhibitor.
Gillman KW, et al. ACS Med Chem Lett. 2010 Mar 22;1(3):120-4. PMID: 24900185.
Effects of Single Doses of Avagacestat (BMS-708163) on Cerebrospinal Fluid Aβ Levels in Healthy Young Men.
Tong G, et al. Clin Drug Investig. 2012 Sep 14. PMID: 23018285.
BMS-708,163 targets presenilin and lacks notch-sparing activity.
Crump CJ, et al. Biochemistry. 2012 Sep 18;51(37):7209-11. PMID: 22931393.
|Related Gamma-secretase Products|
PF-03084014 (Nirogacestat) is a potent and selective γ-secretase inhibitor with IC50 of 6.2 nM.
YO-01027 (Dibenzazepine, DBZ) is a dipeptidic γ-secretase inhibitor with IC50 of 2.6 nM and 2.9 nM for APPL and Notch cleavage, respectively.
LY900009 is a potent Notch inhibitor with IC50 of 0.27 nM.
LY3039478 is a novel and orally bioavailable inhibitor of Notch-1 intracellular domain (N1ICD) cleavage with IC50 of ~1 nM.
FLI-06 is a novel inhibitor of Notch signaling with EC50 of 2.3 μM.
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