Home Neuronal Signaling BACE inhibitor LY2886721 For research use only.

LY2886721

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

LY2886721 Chemical Structure

LY2886721 Chemical Structure

CAS No. 1262036-50-9

Purity & Quality Control

LY2886721 Related Products

Signaling Pathway

BACE Signaling Pathways

BACE Signaling Pathway

Biological Activity

Description LY2886721 is a BACE 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
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. [1] LY2886721 can also targetγ-secretase to nhibit the synthesis of β-amyloid[2]. 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[3]. 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[4].
Cell Research Cell lines HEK293 cells
Concentrations --
Incubation Time Overnight exposure
Method

A human embryonic kidney cell line (HEK293) stably expressing APP751cDNA containing a Swedish mutation (HEK293Swe) was exposed to increasing concentrations of LY2886721 and the amount of amyloid β1–40 (Aβ1-40) and Aβ1-42 measured in the media as an index of BACE1 inhibition. Compound cytotoxicity was assessed using a CellTiter96 Aqueous Non-Radioactive Cell Proliferation assay
In Vivo
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[3]. 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[4].
Animal Research Animal Models young PDAPP transgenic mice
Dosages 1.5 mg/kg
Administration by oral gavage
NCT Number Recruitment Conditions Sponsor/Collaborators Start Date Phases
NCT01807026 Completed
Alzheimer Disease|Healthy Volunteers
Eli Lilly and Company
 March 2013 Phase 1
NCT01534273 Completed
Healthy Volunteers
Eli Lilly and Company
 February 2012 Phase 1
NCT01367262 Completed
Healthy Volunteers
Eli Lilly and Company
 June 2011 Phase 1
NCT01227252 Completed
Alzheimer''s Disease
Eli Lilly and Company
 December 2010 Phase 1
NCT01133405 Completed
Alzheimer''s Disease
Eli Lilly and Company
 June 2010 Phase 1

Chemical Information & Solubility

Molecular Weight 390.41 Formula

C18H16F2N4O2S
CAS No. 1262036-50-9 SDF Download LY2886721 SDF
Smiles C1C2CSC(=NC2(CO1)C3=C(C=CC(=C3)NC(=O)C4=NC=C(C=C4)F)F)N
Storage (From the date of receipt)

In vitro
Batch:

DMSO : 35 mg/mL ( (89.64 mM) Moisture-absorbing DMSO reduces solubility. Please use fresh DMSO.)

Water : Insoluble

Ethanol : Insoluble


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In vivo
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Tech Support

Answers to questions you may have can be found in the inhibitor handling instructions. Topics include how to prepare stock solutions, how to store inhibitors, and issues that need special attention for cell-based assays and animal experiments.

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