| Identification | Back Directory | [Name]
AMG-8718 | [CAS]
1215868-94-2 | [Synonyms]
AMG-8718
AMG 8718
(AMG-8718
(4S)-7'-(2-fluoropyridin-3-yl)-3'-[2-(3-methyloxetan-3-yl)ethynyl]spiro[5H-1,3-oxazole-4,5'-chromeno[2,3-b]pyridine]-2-amine | [Molecular Formula]
C25H19FN4O3 | [MDL Number]
MFCD28902223 | [MOL File]
1215868-94-2.mol | [Molecular Weight]
442.44 |
| Hazard Information | Back Directory | [Description]
AMG-8718 is a potent and orally efficacious BACE1 inhibitor. AMG-8718 produced robust and sustained reductions of CSF and brain Aβ levels in a rat pharmacodynamic model and exhibited significantly reduced potential for QTc elongation in a cardiovascular safety model. BACE1 (β-secretase, memapsin 2, Asp2) has emerged as a promising target for the treatment of Alzheimer's disease. BACE1 is an aspartic protease which functions in the first step of the pathway leading to the production and deposition of amyloid-β peptide (Aβ). BACE1 inhibition has direct implications in the Alzheimer's disease pathology without largely affecting viability. | [Uses]
AMG-8718 is a potent, selective and orally active BACE1 inhibitor with IC50 values of 0.0007, 0.005 μM for BACE1 and BACE2, respectively. AMG-8718 significantly decreases Aβ40 levels in the CSF and brain[1]. | [in vivo]
AMG-8718 (compound 42) (10 mg/kg; p.o.)shows significantly decreases Aβ40 levels in the CSF and brain[1].
AMG-8718 (i.v. for 2 mg/kg or p.o. for 5 mg/kg) shows good bioavailability of 70%, 96%,101% for rats, beagle dog, monkey, respectively[1].
AMG-8718 (30 mg/kg for; p.o.) dose-dependent decreases in both CSF and brain Aβ levels at 4 h time points with 50% Aβ reduction (EC50) values of 18 and 67 nM for CSF and brain respectively in rats[1].
AMG-8718 (2.5, 8, 16 mg/kg; i.v.; a series of three 30 min infusions) shows high unbound plasma concentrations with 0.298, 1.70, 3.62 μM at the end of each infusion in chloralose-anesthetized dogs[1].
Pharmacokinetic Parameters ofAMG-8718 in rats, beagle dog, cynomolgus monkey[1].
| species | Cl (L/h/kg) | Vdss(L/kg) | t1/2(h) | Cmax (μM) | tmax(h) | % F | plasma protein binding (Fu) | | i.v. | | | p.o. | | | | | | rat | 0.33 | 1.1 | 4.8 | 3.8 | 1.7 | 70 | 0.013 | | beagle dog | 0.26 | 1.6 | 5.2 | 8.1 | 1.0 | 96 | 0.038 | | monkey | 0.61 | 2.2 | 7.7 | 6.1 | 1.7 | 101 | 0.054 |
2 mg/kg i.v.; rats (DMSO), dog (1% Tween80/2% HMPC/97% water at pH = 4), cynomolgus monkey (25% HBC/75% water at pH = 4); 5 mg/kg p.o. (1% Tween80/2% HMPC/97% water at pH = 2) [1].
| Animal Model: | Male Sprague-Dawley rats[1] | | Dosage: | 10 mg/kg | | Administration: | Oral gavage | | Result: | Significantly decreased Aβ40 levels in the CSF at the 4 h time point at 69%, produced a robust response in the brain with 48% reduction of Aβ40 levels. |
| Animal Model: | Rats, beagle dog, monkey[1] | | Dosage: | 2, 5 mg/kg | | Administration: | I.v. for 2 mg/kg or p.o. for 5 mg/kg | | Result: | Showed moderate total clearance, moderate Vdss, and half-lives of ca. 5-8 h across all three species, and bioavailability was high (70–101%). |
| Animal Model: | Rats[1] | | Dosage: | 30 mg/kg | | Administration: | P.o. | | Result: | Demonstrated dose-dependent decreases in both CSF and brain Aβ levels at 4 h and 8 h time points. |
| [IC 50]
BACE1: 0.0007 μM (IC50); BACE2: 0.005 μM (IC50) | [References]
[1] Dineen TA,et al. Inhibitors of β-site amyloid precursor protein cleaving enzyme (BACE1): identification of (S)-7-(2-fluoropyridin-3-yl)-3-((3-methyloxetan-3-yl)ethynyl)-5'H-spiro[chromeno[2,3-b]pyridine-5,4'-oxazol]-2'-amine (AMG-8718). J Med Chem. 2014 Dec 11;57(23):9811-31. DOI:10.1021/jm5012676 |
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| Company Name: |
BOC Sciences
|
| Tel: |
1-631-485-4226; 16314854226 |
| Website: |
https://www.bocsci.com |
| Company Name: |
BOC Sciences
|
| Tel: |
16314854226 |
| Website: |
www.bocsci.com |
|