AMG-8718 是一种有效的、选择性的和具有口服活性的BACE1抑制剂，对 BACE1 和 BACE2 的IC50值分别为 0.0007 和 0.005 μM。AMG-8718 显着降低 CSF 和大脑中的 Aβ40水平。
| 生物活性 | AMG-8718 is a potent, selective and orally activeBACE1inhibitor withIC50values of 0.0007, 0.005 μM forBACE1andBACE2, respectively. AMG-8718 significantly decreases Aβ40levels in the CSF and brain[1]. |
| IC50& Target[1] | BACE1 0.0007 μM (IC50) | BACE2 0.005 μM (IC50) |
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体外研究
(In Vitro) | AMG-8718 (compound 42) shows good stability in human and rat liver microsomes, hERG binding activity with an Kivalue of >10 μM[1].
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体内研究
(In Vivo) | AMG-8718 (compound 42) (10 mg/kg; p.o.)shows significantly decreases Aβ40levels 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 Aβ40levels 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. |
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| 运输条件 | Room temperature in continental US; may vary elsewhere. |
| 储存方式 | Please store the product under the recommended conditions in the Certificate of Analysis. |
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