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Fig. 1 · Structure
Cat. No.
A10543
CAS No.
1262036-50-9
Formula
C18H16F2N4O2S
Mol. Weight
390.4

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LY2886721

Cat. No. A10543 CAS 1262036-50-9

BACE1 inhibitor

LY2886721 is a novel potent agent that is used to treat Alzheimer's Disease in preclinical experiments.

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Publications for LY2886721

1 publication citing this product

  1. Naomi Ito, .et al. , Br J Pharmacol, 2017, Mar; 174(5): 386-395 PMID: 28012171
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Biological Activity

Bioactivity / Mechanism

LY2886721 hydrochloride inhibited recombinant BACE1 and BACE2, with substantially weaker activity against cathepsin D, pepsin and renin. These data do not support selectivity for BACE1 over BACE2. The nonclinical salt differs from the catalog free-base composition. [1]

Literature-reported observations and conditions; not Adooq-tested protocols or general treatment recommendations.

Target & Activity

Target Activity Value
BACE

Cellular Effect

Cell Line Activity Value Description Reference
HEK293 IC50 0.0203 μM Inhibition of human BACE1 (1 to 460 residues) expressed in HEK293 cells using mcaFRET peptide as substrate after 20 hrs by FRET assay [PMID: 31786008]
HEK293 IC50 20.3 nM Inhibition of Fc domain of IgG1-fused human BACE1 (1 to 460) expressed in HEK293 cells preincubated for 10 mins followed by enzyme addition measured after 16 to 24 hrs by FRET assay [PMID: 24704031]

In Vitro Studies

In HEK293Swe cells, overnight exposure to LY2886721 hydrochloride lowered secreted Aβ1–40 and Aβ1–42 at similar concentrations, with a much higher reported cytotoxicity threshold. These are cellular Aβ-processing endpoints. [1]

Recombinant BACE inhibition and aspartyl-protease selectivity

Biochemical assay · Purified recombinant human BACE1 and BACE2; cathepsin D, pepsin and renin assays [1]

LY2886721 hydrochloride inhibited BACE1 and BACE2, with weaker inhibition of the other tested aspartyl proteases. It was not selective for BACE1 over BACE2.

Measured endpoints — not treatment concentrations
EndpointReported resultReference
Human BACE1 inhibitionAbsolute IC50 20.3 nM (SD 10.1 nM); n = 10[1]
Human BACE2 inhibitionAbsolute IC50 10.2 nM (SD 4.8 nM); n = 12/14[1]
Cathepsin D inhibitionAbsolute IC50 >300,000 nM; n = 1/6[1]
Pepsin inhibitionAbsolute IC50 >100,000 nM; n = 5[1]
Renin inhibitionAbsolute IC50 >100,000 nM; n = 6[1]

Literature-Reported Treatment Conditions

Treatment concentration
Increasing concentrations in a 10-point inhibition curve; exact series not supplied in the read methods.
Method
In vitro FRET enzyme inhibition
Reported limits
Detailed reaction conditions are referred to May et al. (2011) rather than reproduced here; no conditions borrowed. Unusual n = 12/14 and n = 1/6 notation preserved without reinterpretation.
Methods and source locations

Compound reported in the paper: LY2886721; Compound label in the paper: LY2886721 hydrochloride

Results apply to the paper’s tested material and model. No salt-equivalence, Adooq lot-validation, or clinical efficacy inference.

Table 2, aspartyl protease rows; Methods: Preparation, recombinant assays and selectivity assays; Results: BACE1 and related aspartyl protease inhibition

Human BACE1 inhibition: FRET assay; 10-point inhibition curve fitted with a four-parameter logistic equation. — Table 2, Human BACE1 row; Methods: recombinant and selectivity enzyme assays

Human BACE2 inhibition: FRET assay; 10-point inhibition curve fitted with a four-parameter logistic equation. — Table 2, Human BACE2 row; Methods: recombinant and selectivity enzyme assays

Cathepsin D inhibition: FRET assay; 10-point inhibition curve fitted with a four-parameter logistic equation. — Table 2, Cathepsin D row; Methods: recombinant and selectivity enzyme assays

Pepsin inhibition: FRET assay; 10-point inhibition curve fitted with a four-parameter logistic equation. — Table 2, Pepsin row; Methods: recombinant and selectivity enzyme assays

Renin inhibition: FRET assay; 10-point inhibition curve fitted with a four-parameter logistic equation. — Table 2, Renin row; Methods: recombinant and selectivity enzyme assays

Aβ secretion and cytotoxicity in HEK293Swe cells

Cell-based study · HEK293 cells stably expressing human APP751 carrying the Swedish mutation [1]

Overnight LY2886721 hydrochloride exposure reduced secreted Aβ1–40 and Aβ1–42 at similar concentrations. The matched cytotoxicity assay showed a much higher reported threshold.

Measured endpoints — not treatment concentrations
EndpointReported resultReference
Secreted Aβ1–40Relative IC50 18.5 nM (SD 12.7 nM); n = 9[1]
Secreted Aβ1–42Relative IC50 19.7 nM (SD 10.3 nM); n = 10[1]
CytotoxicityRelative IC50 >100,000 nM; n = 1/9[1]

Literature-Reported Treatment Conditions

Treatment concentration
Increasing concentrations; exact series not supplied in the read text.
Exposure duration
Overnight
Method
Exposure in cell culture; Aβ measured in medium.
Reported limits
Vehicle and exact concentration series are not specified in the read methods. Table 2 labels relative IC50; narrative calls the same Aβ estimates EC50. The table label is retained; slash n notation is uninterpreted.
Methods and source locations

Compound reported in the paper: LY2886721; Compound label in the paper: LY2886721 hydrochloride

Results apply to the paper’s tested material and model. No salt-equivalence, Adooq lot-validation, or clinical efficacy inference.

Table 2, HEK293Swe rows; Methods: cell-based assays; Results: Cellular assays

Secreted Aβ1–40: Conditioned-medium Aβ ELISA — Table 2, HEK293Swe Aβ1–40 row; Cell-based assays methods/results

Secreted Aβ1–42: Conditioned-medium Aβ ELISA — Table 2, HEK293Swe Aβ1–42 row; Cell-based assays methods/results

Cytotoxicity: CellTiter96 Aqueous Non-Radioactive Cell Proliferation assay — Table 2, HEK293Swe cytotox row; Cell-based assays methods/results

In Vivo Studies

In an acute PDAPP mouse study, oral LY2886721 hydrochloride reduced brain Aβ and APP-processing markers. Cortical C99 did not reach significance at the lowest dose, although Aβ and sAPPβ decreased. [1]

A separate intact-rat study using AdooQ-sourced LY2886721 found delayed mechanical allodynia after a single injection, with no acute effect and recovery by day 3. This model-specific sensory effect limits general claims of beneficial BACE inhibition. [2]

Acute brain APP-processing responses in PDAPP mice

Animal study · Female hemizygous PDAPP (APPV717F) mice, 2–3 months old; n = 6–8 per group [1]

A single oral dose lowered hippocampal and cortical Aβ1-x and cortical sAPPβ after 3 h. Cortical C99 was significantly reduced at 10 and 30 mg/kg; the 3 mg/kg C99 effect was not significant.

Measured endpoints — not treatment concentrations
EndpointReported resultReference
Brain Aβ1-x, C99 and sAPPβ relative to vehicleDirectional change and significance Aβ1-x and cortical sAPPβ: reduced at 3, 10 and 30 mg/kg; cortical C99: not significant at 3 mg/kg, reduced at 10 and 30 mg/kg; significant comparisons p < 0.01.[1]

Conditions shared by the study groups

Route
Oral gavage
Frequency
Once
Treatment course
3 h to endpoint
Vehicle
7% Pharmasolve
Study groups and reported outcomes
Group / doseComparatorObserved resultReference
3 mg/kg LY2886721 hydrochloride
3 mg/kg (reported nominal dose)		Vehicle-only group; methods specifies 10 mL/kg vehicle dose volume.Hippocampal/cortical Aβ1-x and cortical sAPPβ reduced (p < 0.01 vs vehicle). Cortical C99 did not reach significance.[1]
10 mg/kg LY2886721 hydrochloride
10 mg/kg (reported nominal dose)		Vehicle-only group; methods specifies 10 mL/kg vehicle dose volume.Hippocampal/cortical Aβ1-x and cortical sAPPβ reduced (p < 0.01 vs vehicle). Cortical C99 reduced (p < 0.01 vs vehicle).[1]
30 mg/kg LY2886721 hydrochloride
30 mg/kg (reported nominal dose)		Vehicle-only group; methods specifies 10 mL/kg vehicle dose volume.Hippocampal/cortical Aβ1-x and cortical sAPPβ reduced (p < 0.01 vs vehicle). Cortical C99 reduced (p < 0.01 vs vehicle).[1]
3 mg/kg LY2886721 hydrochloride
Model: Female hemizygous PDAPP (APPV717F) mice, 2–3 months old; n = 6–8 per group
Reported limits: Hydrochloride used; no salt conversion or cognitive endpoint.
10 mg/kg LY2886721 hydrochloride
Model: Female hemizygous PDAPP (APPV717F) mice, 2–3 months old; n = 6–8 per group
Reported limits: Hydrochloride used; no salt conversion or cognitive endpoint.
30 mg/kg LY2886721 hydrochloride
Model: Female hemizygous PDAPP (APPV717F) mice, 2–3 months old; n = 6–8 per group
Reported limits: Hydrochloride used; no salt conversion or cognitive endpoint.
Methods and source locations

Compound reported in the paper: LY2886721; Compound label in the paper: LY2886721 hydrochloride

Results apply to the paper’s tested material and model. No salt-equivalence, Adooq lot-validation, or clinical efficacy inference.

Figure 2A–D and caption; Results: PDAPP mouse studies; Methods: PDAPP mouse in vivo pharmacology, ELISAs, statistical methods

Brain Aβ1-x, C99 and sAPPβ relative to vehicle: Brain-extract sandwich ELISAs; protein-normalized endpoints; ANOVA with Dunnett post hoc comparisons. — Figure 2A–D; PDAPP mouse Results

3 mg/kg LY2886721 hydrochloride · Figure 2A–D and caption; PDAPP mouse methods/results

10 mg/kg LY2886721 hydrochloride · Figure 2A–D and caption; PDAPP mouse methods/results

30 mg/kg LY2886721 hydrochloride · Figure 2A–D and caption; PDAPP mouse methods/results

Delayed mechanical allodynia in intact rats

Animal study · Intact male Sprague–Dawley rats; overall animal methods: 6–7 weeks, 160–230 g; Figure 5 n = 5 [2]

LY2886721 caused delayed, reversible mechanical hypersensitivity in intact rats. There was no acute effect; the response emerged at 6 h and was no longer present by day 3. At day 1 the dose-response experiment supported a dose-dependent effect.

Measured endpoints — not treatment concentrations
EndpointReported resultReference
Paw withdrawal threshold to mechanical stimulationTime- and dose-dependent response No acute effect; reduction from 6 h through day 2, absent by day 3. Day-1 3 and 10 mg/kg arms significant versus vehicle; 1 mg/kg not marked significant; n = 5.[2]

Conditions shared by the study groups

Route
Intraperitoneal
Frequency
Once
Treatment course
Time course through day 4; dose-response assessed day 1
Vehicle
6.7% DMSO and 5% Tween 20 in saline
Study groups and reported outcomes
Group / doseComparatorObserved resultReference
LY2886721 single-agent dose/time response
10 mg/kg time course; 1, 3 and 10 mg/kg day-1 dose response (Figure 5B)		Matched vehicle injectionDelayed reduction in withdrawal threshold, reversible by day 3; day-1 significance at 3 and 10 mg/kg (p < 0.05), not marked at 1 mg/kg.[2]
LY2886721 single-agent dose/time response
Model: Intact male Sprague–Dawley rats; overall animal methods: 6–7 weeks, 160–230 g; Figure 5 n = 5
Reported limits: No direct target-engagement assay in this pharmacological arm; no proof that BACE1 alone mediates the effect.
Methods and source locations

Compound reported in the paper: LY2886721; Compound label in the paper: LY2886721

Results apply to the paper’s tested material and model. No salt-equivalence, Adooq lot-validation, or clinical efficacy inference.

Figure 5A–B and caption; Results: BACE1 inhibition induces mechanical allodynia; Methods: Animal model, Behavioural test, statistical analyses, Materials

Paw withdrawal threshold to mechanical stimulation: Blinded von Frey assessment; time-course Mann–Whitney U test and dose-response Steel test, p < 0.05; paper data convention mean ± SEM. — Figure 5A–B and caption; Results: BACE1 inhibition induces mechanical allodynia; Behavioural test and Data/statistical analyses

LY2886721 single-agent dose/time response · Figure 5A–B and caption; Animal model drug/vehicle paragraph; Materials

Specifications

Manufacturer Adooq Bioscience
Actions Inhibitor
CAS Number 1262036-50-9
Applications BACE1 inhibitor
Formula C18H16F2N4O2S
Molecular Weight 390.4
SMILES
C1[C@H]2CSC(=N[C@]2(CO1)C3=C(C=CC(=C3)NC(=O)C4=NC=C(C=C4)F)F)N

Storage & Solubility

In Vitro Solubility

Reported Solubility

SolventReported Solubility
DMSO 9 mg/mL (23.05 mM)
Water Insoluble
Ethanol Insoluble

Preparing Stock Solutions

Stock preparation is unavailable for this product molecular weight.

Calculated stock concentrations do not establish solvent solubility. Refer to the reported solubility data for experimental guidance.

Storage

Store powder at -20°C, keep desiccated.
In powder form, the chemical is stable for 36 months.
In solution, store at -20°C and use within 1 month to prevent loss of potency. Aliquot to avoid multiple freeze/thaw cycles.

Research References

  1. [1] Patrick C May, Brian A Willis, Stephen L Lowe, et al. The Potent BACE1 Inhibitor LY2886721 Elicits Robust Central Aβ Pharmacodynamic Responses in Mice, Dogs, and Humans The Journal of Neuroscience (2015). PMID: 25609634 DOI: 10.1523/JNEUROSCI.4129-14.2015 Source material
  2. [2] Naomi Ito, Atsushi Sakai, Noriko Miyake, et al. miR‐15b mediates oxaliplatin‐induced chronic neuropathic pain through BACE1 down‐regulation British Journal of Pharmacology (2017). PMID: 28012171 DOI: 10.1111/bph.13698 Source material

Publications

1 publication citing this product

  1. Naomi Ito, .et al. , Br J Pharmacol, 2017, Mar; 174(5): 386-395 PMID: 28012171

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