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MedKoo Cat#: 510337 | Name: LY2811376
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Description:

WARNING: This product is for research use only, not for human or veterinary use.

LY2811376 is a potent and selective BACE1 inhibitor (IC50 = 239 nM for the synthetic peptide) that demonstrates ~10-fold selectivity over BACE2 and >50-fold selectivity over the aspartyl proteases cathepsin D, pepsin, and renin.3 LY2811376 treatment induces Aβ5-X peptides through alternative amyloid precursor protein cleavage. The β-secretase enzyme, β-site amyloid precursor protein-cleaving enzyme 1 (BACE1), cleaves amyloid precursor protein (APP) in the first step in β-amyloid (Aβ) peptide production. Thus, BACE1 is a key target for candidate disease-modifying treatment of Alzheimer's disease.

Chemical Structure

LY2811376
LY2811376
CAS#1194044-20-6

Theoretical Analysis

MedKoo Cat#: 510337

Name: LY2811376

CAS#: 1194044-20-6

Chemical Formula: C15H14F2N4S

Exact Mass: 320.0907

Molecular Weight: 320.36

Elemental Analysis: C, 56.24; H, 4.40; F, 11.86; N, 17.49; S, 10.01

Price and Availability

Size Price Availability Quantity
5mg USD 325.00 2 weeks
10mg USD 550.00 2 weeks
25mg USD 950.00 2 weeks
50mg USD 1,650.00 2 weeks
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Related CAS #
No Data
Synonym
LY2811376; LY-2811376; LY 2811376.
IUPAC/Chemical Name
(S)-4-(2,4-difluoro-5-(pyrimidin-5-yl)phenyl)-4-methyl-5,6-dihydro-4H-1,3-thiazin-2-amine
InChi Key
MJQMRGWYPNIERM-HNNXBMFYSA-N
InChi Code
InChI=1S/C15H14F2N4S/c1-15(2-3-22-14(18)21-15)11-4-10(12(16)5-13(11)17)9-6-19-8-20-7-9/h4-8H,2-3H2,1H3,(H2,18,21)/t15-/m0/s1
SMILES Code
NC1=N[C@](C)(C2=CC(C3=CN=CN=C3)=C(F)C=C2F)CCS1
Appearance
Solid powder
Purity
>98% (or refer to the Certificate of Analysis)
Shipping Condition
Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.
Storage Condition
Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).
Solubility
Soluble in DMSO, not in water
Shelf Life
>2 years if stored properly
Drug Formulation
This drug may be formulated in DMSO
Stock Solution Storage
0 - 4 C for short term (days to weeks), or -20 C for long term (months).
HS Tariff Code
2934.99.9001
More Info
        
Product Data
Product Data
Instruction
View handling instruction
Biological target:
LY2811376 is the first orally available non-peptidic β-secretase (BACE1) inhibitor with IC50 of 239 nM-249 nM.
In vitro activity:
Finally, this study investigates binding of the inhibitor LY2811376 developed by Eli Lilly to BACE1 and CatD. Surprisingly, in the enzyme active pH range, LY2811376 forms a stronger salt bridge with the catalytic dyad in CatD than in BACE1, which might explain the retinal toxicity of the inhibitor related to off-target inhibition of CatD. Reference: J Comput Chem. 2017 Jun 5;38(15):1260-1269. https://pubmed.ncbi.nlm.nih.gov/28370344/
In vivo activity:
To verify the feasibility of CRANAD-3 for monitoring therapy, this study first used the fast Aβ-lowering drug LY2811376, a well-characterized beta-amyloid cleaving enzyme-1 inhibitor, to treat APP/PS1 mice.This study first tested the capacity of CRANAD-3 with the well-characterized BACE-1 inhibitor LY2811376, which could lead to a 60% decrease in the soluble Aβs in mouse cortex after a single oral dose (30 mg/kg). As expected, the fluorescence signal of CRANAD-3 from APP/PS1 mice (n = 4) after LY2811376 treatment was 33% lower than the signal from the same mice before treatment (Fig. 5 A and B). Reference: Proc Natl Acad Sci U S A. 2015 Aug 4;112(31):9734-9. https://pubmed.ncbi.nlm.nih.gov/26199414/
Solvent mg/mL mM
Solubility
DMF 30.0 93.64
Note: There can be variations in solubility for the same chemical from different vendors or different batches from the same vendor. The following factors can affect the solubility of the same chemical: solvent used for crystallization, residual solvent content, polymorphism, salt versus free form, degree of hydration, solvent temperature. Please use the solubility data as a reference only. Warming and sonication will facilitate dissolving. Still have questions? Please contact our Technical Support scientists.

Preparing Stock Solutions

The following data is based on the product molecular weight 320.36 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.

Recalculate based on batch purity %
Concentration / Solvent Volume / Mass 1 mg 5 mg 10 mg
1 mM 1.15 mL 5.76 mL 11.51 mL
5 mM 0.23 mL 1.15 mL 2.3 mL
10 mM 0.12 mL 0.58 mL 1.15 mL
50 mM 0.02 mL 0.12 mL 0.23 mL
Formulation protocol:
1. Xie S, Wu Y, Qiao Y, Guo Y, Wang J, Hu Z, Zhang Q, Li X, Huang J, Zhou Q, Luo Z, Liu J, Zhu H, Xue Y, Zhang Y. Protoilludane, Illudalane, and Botryane Sesquiterpenoids from the Endophytic Fungus Phomopsis sp. TJ507A. J Nat Prod. 2018 Jun 22;81(6):1311-1320. doi: 10.1021/acs.jnatprod.7b00889. Epub 2018 May 17. PMID: 29771527. 2. Ellis CR, Tsai CC, Lin FY, Shen J. Conformational dynamics of cathepsin D and binding to a small-molecule BACE1 inhibitor. J Comput Chem. 2017 Jun 5;38(15):1260-1269. doi: 10.1002/jcc.24719. Epub 2017 Apr 2. PMID: 28370344; PMCID: PMC5403572. 3. Zhang X, Tian Y, Zhang C, Tian X, Ross AW, Moir RD, Sun H, Tanzi RE, Moore A, Ran C. Near-infrared fluorescence molecular imaging of amyloid beta species and monitoring therapy in animal models of Alzheimer's disease. Proc Natl Acad Sci U S A. 2015 Aug 4;112(31):9734-9. doi: 10.1073/pnas.1505420112. Epub 2015 Jul 21. PMID: 26199414; PMCID: PMC4534214. 4. Qi C, Bao J, Wang J, Zhu H, Xue Y, Wang X, Li H, Sun W, Gao W, Lai Y, Chen JG, Zhang Y. Asperterpenes A and B, two unprecedented meroterpenoids from Aspergillus terreus with BACE1 inhibitory activities. Chem Sci. 2016 Oct 19;7(10):6563-6572. doi: 10.1039/c6sc02464e. Epub 2016 Jun 27. PMID: 28042460; PMCID: PMC5131395.
In vitro protocol:
1. Xie S, Wu Y, Qiao Y, Guo Y, Wang J, Hu Z, Zhang Q, Li X, Huang J, Zhou Q, Luo Z, Liu J, Zhu H, Xue Y, Zhang Y. Protoilludane, Illudalane, and Botryane Sesquiterpenoids from the Endophytic Fungus Phomopsis sp. TJ507A. J Nat Prod. 2018 Jun 22;81(6):1311-1320. doi: 10.1021/acs.jnatprod.7b00889. Epub 2018 May 17. PMID: 29771527. 2. Ellis CR, Tsai CC, Lin FY, Shen J. Conformational dynamics of cathepsin D and binding to a small-molecule BACE1 inhibitor. J Comput Chem. 2017 Jun 5;38(15):1260-1269. doi: 10.1002/jcc.24719. Epub 2017 Apr 2. PMID: 28370344; PMCID: PMC5403572.
In vivo protocol:
1. Zhang X, Tian Y, Zhang C, Tian X, Ross AW, Moir RD, Sun H, Tanzi RE, Moore A, Ran C. Near-infrared fluorescence molecular imaging of amyloid beta species and monitoring therapy in animal models of Alzheimer's disease. Proc Natl Acad Sci U S A. 2015 Aug 4;112(31):9734-9. doi: 10.1073/pnas.1505420112. Epub 2015 Jul 21. PMID: 26199414; PMCID: PMC4534214. 2. Qi C, Bao J, Wang J, Zhu H, Xue Y, Wang X, Li H, Sun W, Gao W, Lai Y, Chen JG, Zhang Y. Asperterpenes A and B, two unprecedented meroterpenoids from Aspergillus terreus with BACE1 inhibitory activities. Chem Sci. 2016 Oct 19;7(10):6563-6572. doi: 10.1039/c6sc02464e. Epub 2016 Jun 27. PMID: 28042460; PMCID: PMC5131395.
1: Filser S, Ovsepian SV, Masana M, Blazquez-Llorca L, Brandt Elvang A, Volbracht C, Müller MB, Jung CK, Herms J. Pharmacological Inhibition of BACE1 Impairs Synaptic Plasticity and Cognitive Functions. Biol Psychiatry. 2014 Oct 29. pii: S0006-3223(14)00793-8. doi: 10.1016/j.biopsych.2014.10.013. [Epub ahead of print] PubMed PMID: 25599931. 2: Lachno DR, Evert BA, Maloney K, Willis BA, Talbot JA, Vandijck M, Dean RA. Validation and Clinical Utility of ELISA Methods for Quantification of Amyloid-β Peptides in Cerebrospinal Fluid Specimens from Alzheimer's Disease Studies. J Alzheimers Dis. 2014 Dec 29. [Epub ahead of print] PubMed PMID: 25547638. 3: Portelius E, Dean RA, Andreasson U, Mattsson N, Westerlund A, Olsson M, Demattos RB, Racke MM, Zetterberg H, May PC, Blennow K. β-site amyloid precursor protein-cleaving enzyme 1(BACE1) inhibitor treatment induces Aβ5-X peptides through alternative amyloid precursor protein cleavage. Alzheimers Res Ther. 2014 Nov 17;6(5-8):75. doi: 10.1186/s13195-014-0075-0. eCollection 2014. PubMed PMID: 25404952; PubMed Central PMCID: PMC4233234. 4: Mikulca JA, Nguyen V, Gajdosik DA, Teklu SG, Giunta EA, Lessa EA, Tran CH, Terak EC, Raffa RB. Potential novel targets for Alzheimer pharmacotherapy: II. Update on secretase inhibitors and related approaches. J Clin Pharm Ther. 2014 Feb;39(1):25-37. doi: 10.1111/jcpt.12112. Epub 2013 Dec 8. Review. PubMed PMID: 24313554. 5: Cheret C, Willem M, Fricker FR, Wende H, Wulf-Goldenberg A, Tahirovic S, Nave KA, Saftig P, Haass C, Garratt AN, Bennett DL, Birchmeier C. Bace1 and Neuregulin-1 cooperate to control formation and maintenance of muscle spindles. EMBO J. 2013 Jul 17;32(14):2015-28. doi: 10.1038/emboj.2013.146. Epub 2013 Jun 21. PubMed PMID: 23792428; PubMed Central PMCID: PMC3715864. 6: Liu X, Wong H, Scearce-Levie K, Watts RJ, Coraggio M, Shin YG, Peng K, Wildsmith KR, Atwal JK, Mango J, Schauer SP, Regal K, Hunt KW, Thomas AA, Siu M, Lyssikatos J, Deshmukh G, Hop CE. Mechanistic pharmacokinetic-pharmacodynamic modeling of BACE1 inhibition in monkeys: development of a predictive model for amyloid precursor protein processing. Drug Metab Dispos. 2013 Jul;41(7):1319-28. doi: 10.1124/dmd.112.050864. Epub 2013 Apr 12. PubMed PMID: 23584887. 7: Lu Y, Barton HA, Leung L, Zhang L, Hajos-Korcsok E, Nolan CE, Liu J, Becker SL, Wood KM, Robshaw AE, Taylor CK, O'Neill BT, Brodney MA, Riddell D. Cerebrospinal fluid β-Amyloid turnover in the mouse, dog, monkey and human evaluated by systematic quantitative analyses. Neurodegener Dis. 2013;12(1):36-50. doi: 10.1159/000341217. Epub 2012 Aug 21. PubMed PMID: 22922480. 8: Lachno DR, Emerson JK, Vanderstichele H, Gonzales C, Martényi F, Konrad RJ, Talbot JA, Lowe SL, Oefinger PE, Dean RA. Validation of a multiplex assay for simultaneous quantification of amyloid-β peptide species in human plasma with utility for measurements in studies of Alzheimer's disease therapeutics. J Alzheimers Dis. 2012;32(4):905-18. doi: 10.3233/JAD-2012-121075. PubMed PMID: 22886018. 9: May PC, Dean RA, Lowe SL, Martenyi F, Sheehan SM, Boggs LN, Monk SA, Mathes BM, Mergott DJ, Watson BM, Stout SL, Timm DE, Smith Labell E, Gonzales CR, Nakano M, Jhee SS, Yen M, Ereshefsky L, Lindstrom TD, Calligaro DO, Cocke PJ, Greg Hall D, Friedrich S, Citron M, Audia JE. Robust central reduction of amyloid-β in humans with an orally available, non-peptidic β-secretase inhibitor. J Neurosci. 2011 Nov 16;31(46):16507-16. doi: 10.1523/JNEUROSCI.3647-11.2011. PubMed PMID: 22090477.