LY 411575 | LY411575 | LSN-411575 | CAS#209984-57-6 | γ-secretase inhibitor

MedKoo Cat#: 526741 | Name: LY-411575

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Description:

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

LY 411575, also known as LSN-411575, is potent, cell permeable and selective γ-secretase inhibitor that reduces Aβ/42 after acute or chronic treatment, and blocks Notch activation. The gamma secretase inhibitor, activating pPKC alpha intracellular pathway could be suggested to prevent or reduce downstream toxic events, representing a useful strategy to counteract Alzheimer's disease.

Chemical Structure

LY-411575

CAS#209984-57-6

Theoretical Analysis

MedKoo Cat#: 526741

Name: LY-411575

CAS#: 209984-57-6

Chemical Formula: C26H23F2N3O4

Exact Mass: 479.1657

Molecular Weight: 479.48

Elemental Analysis: C, 65.13; H, 4.84; F, 7.92; N, 8.76; O, 13.35

Price and Availability

Size	Price	Availability
25mg	USD 250.00	2 Weeks
50mg	USD 450.00	2 Weeks
100mg	USD 750.00	2 Weeks
200mg	USD 1,250.00	2 Weeks
500mg	USD 2,450.00	2 Weeks
1g	USD 3,850.00	2 Weeks
2g	USD 6,450.00	2 Weeks

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Synonym

LY 411575; LY-411575; LY411575; LSN-411575; LSN 411575; LSN411575.

IUPAC/Chemical Name

N2-[(2S)-2-(3,5-difluorophenyl)-2-hydroxyethanoyl]-N1-[(7S)-5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl]-L-alaninamide

InChi Key

ULSSJYNJIZWPSB-CVRXJBIPSA-N

InChi Code

InChI=1S/C26H23F2N3O4/c1-14(29-25(34)23(32)15-11-16(27)13-17(28)12-15)24(33)30-22-20-9-4-3-7-18(20)19-8-5-6-10-21(19)31(2)26(22)35/h3-14,22-23,32H,1-2H3,(H,29,34)(H,30,33)/t14-,22-,23-/m0/s1

SMILES Code

C[C@@H](C(N[C@H]1C2=CC=CC=C2C3=CC=CC=C3N(C)C1=O)=O)NC([C@H](C4=CC(F)=CC(F)=C4)O)=O

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

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:

LY-411575 is a potent γ-secretase inhibitor with IC50 of 0.078 nM/0.082 nM (membrane/cell-based), and also inhibits Notch S3 cleavage with IC50 of 0.39 nM.

In vitro activity:

Production of intracellular core protein and supernatant infectious viral particles from HCV-infected cells was significantly impaired by LY411575 in a dose-dependent manner (half maximum inhibitory concentration = 0.27 μM, cytotoxic concentration of the extracts to cause death to 50% of viable cells > 10 μM). Reference: Microbiol Immunol. 2016 Nov;60(11):740-753. https://pubmed.ncbi.nlm.nih.gov/27797115/

In vivo activity:

Six-day oral administration of the gamma-secretase inhibitor N(2)-[(2S)-2-(3,5-difluorophenyl)-2-hydroxyethanoyl]-N(1)-[(7S)-5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl]-l-alaninamide (LY411,575) reduced cortical Abeta(40) in young (preplaque) transgenic CRND8 mice (ED(50) approximately 0.6 mg/kg) and produced significant thymus atrophy and intestinal goblet cell hyperplasia at higher doses (>3 mg/kg). Three-week treatment with 1 mg/kg LY411,575 reduced cortical Abeta(40) by 69% without inducing intestinal effects, although a previously unreported change in coat color was observed. Reference: J Pharmacol Exp Ther. 2006 Dec;319(3):1133-43. https://pubmed.ncbi.nlm.nih.gov/16946102/

	Solvent	mg/mL	mM
Solubility
	DMF	10.0	20.86
	DMSO	64.2	133.82
	Ethanol	13.0	27.11

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 479.48 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.

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. Zhang J, Yuan G, Dong M, Zhang T, Hua G, Zhou Q, Shi W. Notch signaling modulates proliferative vitreoretinopathy via regulating retinal pigment epithelial-to-mesenchymal transition. Histochem Cell Biol. 2017 Mar;147(3):367-375. doi: 10.1007/s00418-016-1484-x. Epub 2016 Sep 7. PMID: 27600720. 2. Otoguro T, Tanaka T, Kasai H, Yamashita A, Moriishi K. Inhibitory effect of presenilin inhibitor LY411575 on maturation of hepatitis C virus core protein, production of the viral particle and expression of host proteins involved in pathogenicity. Microbiol Immunol. 2016 Nov;60(11):740-753. doi: 10.1111/1348-0421.12448. PMID: 27797115. 3. Hyde LA, McHugh NA, Chen J, Zhang Q, Manfra D, Nomeir AA, Josien H, Bara T, Clader JW, Zhang L, Parker EM, Higgins GA. Studies to investigate the in vivo therapeutic window of the gamma-secretase inhibitor N2-[(2S)-2-(3,5-difluorophenyl)-2-hydroxyethanoyl]-N1-[(7S)-5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl]-L-alaninamide (LY411,575) in the CRND8 mouse. J Pharmacol Exp Ther. 2006 Dec;319(3):1133-43. doi: 10.1124/jpet.106.111716. Epub 2006 Aug 31. PMID: 16946102. 4. Wong GT, Manfra D, Poulet FM, Zhang Q, Josien H, Bara T, Engstrom L, Pinzon-Ortiz M, Fine JS, Lee HJ, Zhang L, Higgins GA, Parker EM. Chronic treatment with the gamma-secretase inhibitor LY-411,575 inhibits beta-amyloid peptide production and alters lymphopoiesis and intestinal cell differentiation. J Biol Chem. 2004 Mar 26;279(13):12876-82. doi: 10.1074/jbc.M311652200. Epub 2004 Jan 6. PMID: 14709552.

In vitro protocol:

In vivo protocol:

1. Hyde LA, McHugh NA, Chen J, Zhang Q, Manfra D, Nomeir AA, Josien H, Bara T, Clader JW, Zhang L, Parker EM, Higgins GA. Studies to investigate the in vivo therapeutic window of the gamma-secretase inhibitor N2-[(2S)-2-(3,5-difluorophenyl)-2-hydroxyethanoyl]-N1-[(7S)-5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl]-L-alaninamide (LY411,575) in the CRND8 mouse. J Pharmacol Exp Ther. 2006 Dec;319(3):1133-43. doi: 10.1124/jpet.106.111716. Epub 2006 Aug 31. PMID: 16946102. 2. Wong GT, Manfra D, Poulet FM, Zhang Q, Josien H, Bara T, Engstrom L, Pinzon-Ortiz M, Fine JS, Lee HJ, Zhang L, Higgins GA, Parker EM. Chronic treatment with the gamma-secretase inhibitor LY-411,575 inhibits beta-amyloid peptide production and alters lymphopoiesis and intestinal cell differentiation. J Biol Chem. 2004 Mar 26;279(13):12876-82. doi: 10.1074/jbc.M311652200. Epub 2004 Jan 6. PMID: 14709552.

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Learning by failing: ideas and concepts to tackle γ-secretases in Alzheimer's disease and beyond. Annu Rev Pharmacol Toxicol. 2015;55:419-37. doi: 10.1146/annurev-pharmtox-010814-124309. Epub 2014 Oct 1. Review. PubMed PMID: 25292430. 5: Liu Q, Waltz S, Woodruff G, Ouyang J, Israel MA, Herrera C, Sarsoza F, Tanzi RE, Koo EH, Ringman JM, Goldstein LS, Wagner SL, Yuan SH. Effect of potent γ-secretase modulator in human neurons derived from multiple presenilin 1-induced pluripotent stem cell mutant carriers. JAMA Neurol. 2014 Dec;71(12):1481-9. doi: 10.1001/jamaneurol.2014.2482. PubMed PMID: 25285942; PubMed Central PMCID: PMC4374637. 6: Henley DB, Sundell KL, Sethuraman G, Dowsett SA, May PC. Safety profile of semagacestat, a gamma-secretase inhibitor: IDENTITY trial findings. Curr Med Res Opin. 2014 Oct;30(10):2021-32. doi: 10.1185/03007995.2014.939167. Epub 2014 Jul 14. 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PubMed PMID: 24672754; PubMed Central PMCID: PMC3964281. 10: Henley DB, Sundell KL, Sethuraman G, Schneider LS. Adverse events and dropouts in Alzheimer's disease studies: what can we learn? Alzheimers Dement. 2015 Jan;11(1):24-31. doi: 10.1016/j.jalz.2013.11.008. Epub 2014 Mar 6. PubMed PMID: 24613705. 11: Beggiato S, Giuliani A, Sivilia S, Lorenzini L, Antonelli T, Imbimbo BP, Giardino L, Calzà L, Ferraro L. CHF5074 and LY450139 sub-acute treatments differently affect cortical extracellular glutamate levels in pre-plaque Tg2576 mice. Neuroscience. 2014 Apr 25;266:13-22. doi: 10.1016/j.neuroscience.2014.01.065. Epub 2014 Feb 12. PubMed PMID: 24530449. 12: Ito G, Okamoto R, Murano T, Shimizu H, Fujii S, Nakata T, Mizutani T, Yui S, Akiyama-Morio J, Nemoto Y, Okada E, Araki A, Ohtsuka K, Tsuchiya K, Nakamura T, Watanabe M. Lineage-specific expression of bestrophin-2 and bestrophin-4 in human intestinal epithelial cells. 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PubMed PMID: 24090904. 16: Doody RS, Raman R, Farlow M, Iwatsubo T, Vellas B, Joffe S, Kieburtz K, He F, Sun X, Thomas RG, Aisen PS; Alzheimer's Disease Cooperative Study Steering Committee, Siemers E, Sethuraman G, Mohs R; Semagacestat Study Group. A phase 3 trial of semagacestat for treatment of Alzheimer's disease. N Engl J Med. 2013 Jul 25;369(4):341-50. doi: 10.1056/NEJMoa1210951. PubMed PMID: 23883379. 17: Winston CN, Chellappa D, Wilkins T, Barton DJ, Washington PM, Loane DJ, Zapple DN, Burns MP. Controlled cortical impact results in an extensive loss of dendritic spines that is not mediated by injury-induced amyloid-beta accumulation. J Neurotrauma. 2013 Dec 1;30(23):1966-72. doi: 10.1089/neu.2013.2960. Epub 2013 Oct 12. PubMed PMID: 23879560; PubMed Central PMCID: PMC3837436. 18: Haug KG, Staab A, Dansirikul C, Lehr T. A semi-physiological model of amyloid-β biosynthesis and clearance in human cerebrospinal fluid: a tool for alzheimer's disease research and drug development. J Clin Pharmacol. 2013 Jul;53(7):691-8. doi: 10.1002/jcph.91. Epub 2013 May 27. PubMed PMID: 23712554. 19: Schellekens H, McNamara O, Dinan TG, McCarthy JV, McGlacken GP, Cryan JF. Semagacestat, a γ-secretase inhibitor, activates the growth hormone secretagogue (GHS-R1a) receptor. J Pharm Pharmacol. 2013 Apr;65(4):528-38. doi: 10.1111/jphp.12010. Epub 2012 Nov 27. PubMed PMID: 23488781. 20: Grotek B, Wehner D, Weidinger G. Notch signaling coordinates cellular proliferation with differentiation during zebrafish fin regeneration. Development. 2013 Apr;140(7):1412-23. doi: 10.1242/dev.087452. Epub 2013 Mar 5. PubMed PMID: 23462472.