Semagacestat | LY450139 | LY4501 | CAS# 425386-60-3 | γ-Secretase Inhibitor

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

MedKoo CAT#: 315251

CAS#: 425386-60-3 (free base)

Description: Semagacestat, also known as LY450139 or LY4501; was a candidate drug for a causal therapy against Alzheimer's disease. It was originally developed by Eli Lilly and Ãlan, and clinical trials were conducted by Eli Lilly. Phase III trials included over 3000 patients, but in August 2010, a disappointing interim analysis, in which semagacestat performed less well than the placebo, led to investigators being instructed to tell subjects to stop taking the drug.

Chemical Structure

Semagacestat

CAS# 425386-60-3 (free base)

Product data Instruction

Theoretical Analysis

MedKoo Cat#: 315251
Name: Semagacestat
CAS#: 425386-60-3 (free base)
Chemical Formula: C19H27N3O4
Exact Mass: 361.20
Molecular Weight: 361.442
Elemental Analysis: C, 63.14; H, 7.53; N, 11.63; O, 17.71

Price and Availability

Size	Price	Availability	Quantity
5g	USD -1
10mg	USD 190
25mg	USD 350
50mg	USD 550
100mg	USD 950
200mg	USD 1650
500mg	USD 2650
1g	USD 3650
2g	USD 4650
Bulk inquiry Welcome, Customer: Please do not inquire quote if your intended use is for a patient since our products are for research use and for chemical synthesis use, not for human use . For in-stock products, we listed price in the web page. You may inquire prices for which sizes were not listed. If no price is listed, this means the product is not in stock at the moment, which may be available via custom synthesis. For cost-effective reason, minimum order of 1g is requested (typically very expensive). The lead time is usually 2-4 months. Quote of less than 1g will not be provided. MedKoo may not offer quote for below reasons: (1) current available synthetic method appears to be extremely expensive which is obviously not affordable to most customers; (2) Key raw material to make the product is temporally not available; (3) DEA controlled substances; (4) the product is under patent protection in customer’s country.

Related CAS #: Semagacestat dihydrate 425386-60-3 (free base)

Synonym: LY4501; LY-4501; LY 4501; LY450139; LY-450139; LY 450139; Semagacestat.

IUPAC/Chemical Name: (S)-2-hydroxy-3-methyl-N-((S)-1-(((S)-3-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-yl)amino)-1-oxopropan-2-yl)butanamide

InChi Key: PKXWXXPNHIWQHW-RCBQFDQVSA-N

InChi Code: InChI=1S/C19H27N3O4/c1-11(2)16(23)18(25)20-12(3)17(24)21-15-14-8-6-5-7-13(14)9-10-22(4)19(15)26/h5-8,11-12,15-16,23H,9-10H2,1-4H3,(H,20,25)(H,21,24)/t12-,15-,16-/m0/s1

SMILES Code: CC(C)[C@H](O)C(N[C@@H](C)C(N[C@@H]1C(N(C)CCC2=CC=CC=C12)=O)=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).

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Product Data:

Product Data

Instruction:

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Biological target:	Semagacestat is a potent inhibitor of γ-secretase that blocks the production of Aβ38, Aβ40, and Aβ42 with IC50 values of 12.0, 12.1, and 10.9 nM, respectively. It also blocks Notch signaling (IC50 = 14.1 nM).
In vitro activity:	This study suggests a novel mechanism of action for semagacestat via modest GHS-R1a receptor activation. Semagacestat and its precursor were shown to activate the GHS-R1a receptor. Moreover, a synergistic GHS-R1a receptor activation was shown following a combined exposure to ghrelin and semagacestat. In addition, GHS-R1a receptor internalization was observed upon exposure to semagacestat and its precursor. Reference: J Pharm Pharmacol. 2013 Apr;65(4):528-38. https://pubmed.ncbi.nlm.nih.gov/23488781/
In vivo activity:	This study provides reasoning behind why the Eli Lilly clinical trial for semagacestat failed. The results of this study demonstrated that semagacestat is a pseudo-γ-secretase inhibitor (GSI) and not a true GSI, which would impact trial hypothesis, methods, and outcomes. Semagacestat increased intracellular byproduct peptides, produced along with Aβ through serial γ-cleavage of βAPP, as well as intracellular long Aβ species, in cell-based and in vivo studies of AD model mice. Reference: Cell Rep. 2017 Oct 3;21(1):259-273. https://pubmed.ncbi.nlm.nih.gov/28978478/

Solubility Data

	Solvent	Max Conc. mg/mL	Max Conc. mM
Solubility
	DMF	25.0	69.17
	DMSO	25.0	69.17
	Ethanol	1.0	2.77

Preparing Stock Solutions

The following data is based on the product molecular weight 361.44 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. 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. PMID: 23488781. 2. Tagami S, Yanagida K, Kodama TS, Takami M, Mizuta N, Oyama H, Nishitomi K, Chiu YW, Okamoto T, Ikeuchi T, Sakaguchi G, Kudo T, Matsuura Y, Fukumori A, Takeda M, Ihara Y, Okochi M. Semagacestat Is a Pseudo-Inhibitor of γ-Secretase. Cell Rep. 2017 Oct 3;21(1):259-273. doi: 10.1016/j.celrep.2017.09.032. PMID: 28978478. 3. Rosenberg PB, Lanctôt KL, Herrmann N, Mintzer JE, Porsteinsson AP, Sun X, Raman R. Changes in Neuropsychiatric Inventory Associated with Semagacestat Treatment of Alzheimer's Disease. J Alzheimers Dis. 2016 Aug 10;54(1):373-81. doi: 10.3233/JAD-151113. PMID: 27567808.
In vitro protocol:	1. 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. PMID: 23488781.
In vivo protocol:	1. Tagami S, Yanagida K, Kodama TS, Takami M, Mizuta N, Oyama H, Nishitomi K, Chiu YW, Okamoto T, Ikeuchi T, Sakaguchi G, Kudo T, Matsuura Y, Fukumori A, Takeda M, Ihara Y, Okochi M. Semagacestat Is a Pseudo-Inhibitor of γ-Secretase. Cell Rep. 2017 Oct 3;21(1):259-273. doi: 10.1016/j.celrep.2017.09.032. PMID: 28978478. 2. Rosenberg PB, Lanctôt KL, Herrmann N, Mintzer JE, Porsteinsson AP, Sun X, Raman R. Changes in Neuropsychiatric Inventory Associated with Semagacestat Treatment of Alzheimer's Disease. J Alzheimers Dis. 2016 Aug 10;54(1):373-81. doi: 10.3233/JAD-151113. PMID: 27567808.

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1: Ross JS, Imbimbo BP. Are γ-secretase inhibitors detrimental for Alzheimer's disease patients? J Alzheimers Dis. 2010 Jan 1;22(2):401-4. PubMed PMID: 21149978.

2: Kelleher RJ 3rd, Shen J. Genetics. Gamma-secretase and human disease. Science. 2010 Nov 19;330(6007):1055-6. PubMed PMID: 21097925.

3: Cummings J. What can be inferred from the interruption of the semagacestat trial for treatment of Alzheimer's disease? Biol Psychiatry. 2010 Nov 15;68(10):876-8. PubMed PMID: 21035622.

4: Samson K. NerveCenter: Phase III Alzheimer trial halted: Search for therapeutic biomarkers continues. Ann Neurol. 2010 Oct;68(4):A9-A12. PubMed PMID: 20976761.

5: Extance A. Alzheimer's failure raises questions about disease-modifying strategies. Nat Rev Drug Discov. 2010 Oct;9(10):749-51. PubMed PMID: 20885394.

6: Portelius E, Van Broeck B, Andreasson U, Gustavsson MK, Mercken M, Zetterberg H, Borghys H, Blennow K. Acute effect on the Aβ isoform pattern in CSF in response to γ-secretase modulator and inhibitor treatment in dogs. J Alzheimers Dis. 2010;21(3):1005-12. PubMed PMID: 20634579.

7: Shitaka Y, Mitani Y, Nagakura A, Miyake A, Matsuoka N. [Progress in the development of anti-amyloid drugs for treatment of Alzheimer's disease.]. Nippon Yakurigaku Zasshi. 2010 Jul;136(1):15-20. Review. Japanese. PubMed PMID: 20628208.

8: Panza F, Frisardi V, Imbimbo BP, Capurso C, Logroscino G, Sancarlo D, Seripa D, Vendemiale G, Pilotto A, Solfrizzi V. REVIEW: γ-Secretase inhibitors for the treatment of Alzheimer's disease: The current state. CNS Neurosci Ther. 2010 Oct;16(5):272-84. doi: 10.1111/j.1755-5949.2010.00164.x. Epub 2010 Jun 16. PubMed PMID: 20560993.

9: Portelius E, Dean RA, Gustavsson MK, Andreasson U, Zetterberg H, Siemers E, Blennow K. A novel Abeta isoform pattern in CSF reflects gamma-secretase inhibition in Alzheimer disease. Alzheimers Res Ther. 2010 Mar 29;2(2):7. PubMed PMID: 20350302; PubMed Central PMCID: PMC2876785.

10: Raybon JJ, Albright CF. In response to "a gamma-secretase inhibitor decreases amyloid-beta production in the central nervous system". Ann Neurol. 2010 Jan;67(1):143-4; author reply 144-5. PubMed PMID: 20186950.

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