[CAS NO. 1262036-50-9] LY2886721

Name: LY2886721
Brand: Arctom Scientific
SKU: SLK-S2156

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PRODUCTS SPECIFICATIONS [1262036-50-9]

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Catalog

SLK-S2156

Brand

Selleck

CAS

1262036-50-9

DESCRIPTION [1262036-50-9]

Overview

MDL	MFCD22124078
Molecular Weight	390.41
Molecular Formula	C18H16F2N4O2S
SMILES	FC=1C([C@@]23[C@@](COC2)(CSC(N)=N3)[H])=CC(NC(=O)C4=CC=C(F)C=N4)=CC1

For research use only.

Storage

3 years,-20°C,powder
1 years,-80°C,in solvent

Shipping

Room temperature shipping(Stability testing shows this product can be shipped without any cooling measures.)

Preparing Stock Solutions

Concentration Volume Mass	1 mg	5 mg	10 mg
1 mM	2.5614 mL	12.8070 mL	25.6141 mL
5 mM	0.5123 mL	2.5614 mL	5.1228 mL
10 mM	0.2561 mL	1.2807 mL	2.5614 mL
50 mM	0.0512 mL	0.2561 mL	0.5123 mL

Description

LY2886721 is a inhibitor used for the treatment of Alzheimer's Disease. Phase 1/2.

Targets

BACE2 ^[4] (Cell-free assay)	BACE1 ^[4] (Cell-free assay)
10.2 nM	20.3 nM

In vitro

LY2886721 is an oral, small molecule of β-site amyloid protein cleaving enzyme (BACE) inhibitor with the potential to inhibit the synthesis of β-amyloid and thereby to slow the clinical progression of AD. LY2886721 can also targetγ-secretase to nhibit the synthesis of β-amyloid. LY2886721 inhibits recombinant hBACE1 with an IC50 of 20.3 nM. In cellular assays, LY2886721 inhibits Abeta with an IC50 of 18.7 nM and 10.7 nM, HEK293Swe and PDAPP neuronal culture, respectively. LY2886721 has high selectivity against key off-target proteases, which efficiently translates in vitro activity into robust in vivo amyloid β lowering in nonclinical animal models. Assessment of LY2886721 activity against hBACE2 demonstrates an IC50 of 10.2 nM. Assessment of LY2886721 activity against cathepsin D, pepsin, renin, or other important aspartyl proteases shows essentially no inhibition (IC50 >100,000 nM), suggesting that activity against these common aspartyl proteases is unlikely to be significant.

In vivo

Oral administration of LY2886721 to PDAPP mice produces dose-dependent reductions in brain Abeta, C99 and sAPPbeta. Brain Abeta levels are decreased ∼20%-65% relative to vehicle-treated groups three hours after a 3-30 mg/kg dose of LY2886721. Brain C99 and sAPPb levels also are reduced in a dose-dependent manner consistent with BACE1 inhibition in vivo. The pharmacodynamic responses to LY2886721 persists out to 9 hours post dose in brains of PDAPP mice. Pharmacodynamic studies in beagle dog reveal robust and sustained reductions in plasma Abeta following 1 mg/kg LY2886721 dosing. Central effects of BACE1 inhibition in dog are manifested by a 50% reduction in CSF Abeta at 9 hours after a 0.5 mg/kg dose of LY2886721. The geometric mean terminal elimination t1/2 is determined to be 17.2 h (range 8.19-36.3 h). The geometric mean apparent oral clearance is 34.8 L/h (38% CV) and the apparent volume of distribution during the terminal phase was 863 L (56% CV) across dose levels. LY2886721 is freely permeable across the blood-brain barrier.

References

[1] Adru studies, 2012
[2] Townsend M, et al. J Alzheimers Dis, 2011, 24 Suppl 2, 43-52.
[3] Patrick May, et al. The journal of the Alzheimer's association. 2012, 8(4):Suppl P95.
[4] May PC, et al. J Neurosci. 2015, 35(3):1199-210.

Synonyms

2-Pyridinecarboxamide, N-[3-[(4aS,7aS)-2-amino-4a,5-dihydro-4H-furo[3,4-d][1,3]thiazin-7a(7H)-yl]-4-fluorophenyl]-5-fluoro-

N-[3-[(4aS,7aS)-2-Amino-4a,5-dihydro-4H-furo[3,4-d][1,3]thiazin-7a(7H)-yl]-4-fluorophenyl]-5-fluoro-2-pyridinecarboxamide

LY 2886721