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|
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.
Semagacestat (LY450139) is a γ-secretase blocker for Aβ42, Aβ40 and Aβ38 with IC50 of 10.9 nM, 12.1 nM and 12.0 nM, respectively.
Products are for research use only. Not for human use. We do not sell to patients.
© Copyright 2010-2017 AbMole BioScience. All Rights Reserved.