AMG-8718 is a potent, selective and orally bioactive BACE1 inhibitor (antagonist) with IC50s of 0.0007 and 0.005 µM for BACE1 and BACE2, respectively. AMG-8718 significantly reduces Aβ40 levels in CSF and brain.

Physicochemical Properties

Molecular Formula	C25H19FN4O3
Molecular Weight	442.441768884659
Exact Mass	442.144
CAS #	1215868-94-2
PubChem CID	45254510
Appearance	Typically exists as solid at room temperature
Density	1.4±0.1 g/cm3
Boiling Point	673.7±65.0 °C at 760 mmHg
Flash Point	361.2±34.3 °C
Vapour Pressure	0.0±2.1 mmHg at 25°C
Index of Refraction	1.699
LogP	2.47
Hydrogen Bond Donor Count	1
Hydrogen Bond Acceptor Count	7
Rotatable Bond Count	3
Heavy Atom Count	33
Complexity	866
Defined Atom Stereocenter Count	1
SMILES	FC1C(=CC=CN=1)C1C=CC2=C(C=1)[C@@]1(COC(N)=N1)C1=CC(C#CC3(C)COC3)=CN=C1O2
InChi Key	GKKFBOARESVMBW-VWLOTQADSA-N
InChi Code	InChI=1S/C25H19FN4O3/c1-24(12-31-13-24)7-6-15-9-19-22(29-11-15)33-20-5-4-16(17-3-2-8-28-21(17)26)10-18(20)25(19)14-32-23(27)30-25/h2-5,8-11H,12-14H2,1H3,(H2,27,30)/t25-/m0/s1
Chemical Name	(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
HS Tariff Code	2934.99.9001
Storage	Powder-20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month
Shipping Condition	Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Biological Activity

ln Vitro	In rat and human liver microsomes, AMG-8718 (compound 42) shows good stability with a Ki value of hERG binding activity >10 µM [1].
ln Vivo	AMG-8718 (Compound 42) (10 mg/kg; oral) significantly lowers Aβ40 levels in CSF and brain [1]. AMG-8718 (2 mg/kg intravenously or 5 mg/kg orally) displays good bioavailability in rats, beagle dogs, and monkeys, which are 70%, 96%, and 101% correspondingly [1]. AMG-8718 (30 mg/kg; oral) dose-dependently reduced CSF and brain Aβ levels at the 4-hour time point, with 50% Aβ reduction (EC50) values of 18 and 67 nM in rat CSF and brain, respectively [ 1 ]. AMG-8718 (2.5, 8, 16 mg/kg; intravenously; a series of three 30-minute infusions) revealed increased unbound plasma concentrations at the end of each infusion in chloralose-anesthetized dogs, respectively. are 0.298, 1.70, 3.62 µM[1]. Pharmacokinetic characteristics of AMG-8718 in rats, Beagle dogs, and cynomolgus monkeys [1]. Type Cl (L/h/kg) Vdss(L/kg) t1/2(h) Cmax (μM) tmax(h) % F Plasma protein binding (Fu) ivpo Rat 0.33 1.1 4.8 3.8 1.7 70 0.013 Beagle 0.26 1.6 5.2 8.1 1.0 96 0.038 Monkey0.61 2.2 7.7 6.1 1.7 101 0.054 2 mg/kg intravenously; rat (DMSO), dog (1% Tween80/2% HMPC/97% water, pH = 4), cynomolgus monkey (25% HBC/75% water, pH = 4); 5 mg/kg PO (1% Tween80/2% HMPC/97% water, pH = 2) [1].
Animal Protocol	Animal/Disease Models: Male SD (SD (Sprague-Dawley)) rat [1] Doses: 10 mg/kg Route of Administration: po (oral gavage) Experimental Results: Aβ40 levels in CSF were Dramatically diminished by 69% at the 4-hour time point, and a strong response of 48% Aβ40 was produced in the brain level decreases. Animal/Disease Models: Rats, beagles, monkeys [1] Doses: 2, 5 mg/kg Route of Administration: intravenous (iv) (iv)injection of 2 mg/kg or oral administration of 5 mg/kg Experimental Results: demonstrated moderate total clearance rate, moderate Vdss The bioavailability and half-life of all three species were approximately 5-8 hrs (hrs (hours)) (70-101%). Animal/Disease Models: Rat[1] Doses: 30 mg/kg Route of Administration: Po Experimental Results: There was a dose-dependent decrease in CSF and brain Aβ levels at the 4-hour and 8-hour time points.
References	[1]. 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 D.

Solubility Data

Solubility (In Vitro)

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

Solubility (In Vivo)

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples. Injection Formulations (e.g. IP/IV/IM/SC) Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] *Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline) Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline) Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline) Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil) Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Oral Formulations Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). Oral Formulation 3: Dissolved in PEG400 Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose Oral Formulation 6: Mixing with food powders Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.  (Please use freshly prepared in vivo formulations for optimal results.)

Preparing Stock Solutions		1 mg	5 mg	10 mg
	1 mM	2.2602 mL	11.3010 mL	22.6019 mL
	5 mM	0.4520 mL	2.2602 mL	4.5204 mL
	10 mM	0.2260 mL	1.1301 mL	2.2602 mL

*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.