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

MedKoo Cat#: 315251 | Name: Semagacestat

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Description:

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

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)

Theoretical Analysis

MedKoo Cat#: 315251

Name: Semagacestat

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

Chemical Formula: C19H27N3O4

Exact Mass: 361.2002

Molecular Weight: 361.44

Elemental Analysis: C, 63.14; H, 7.53; N, 11.63; O, 17.71

Price and Availability

Size	Price	Availability	Quantity
10mg	USD 190.00
25mg	USD 350.00
50mg	USD 550.00
100mg	USD 950.00
200mg	USD 1,650.00
500mg	USD 2,650.00
1g	USD 3,650.00
2g	USD 4,650.00

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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).

HS Tariff Code

More Info

Product Data

Product Data

Instruction

View handling instruction

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/

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

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 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:

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.

1: Zhou X, Liu Z, Bai G, Dazhang B, Zhao P, Wang X, Jiang G. Bioinformatics analysis of the potential receptor and therapeutic drugs for Alzheimer's disease with comorbid Parkinson's disease. Front Aging Neurosci. 2024 Jun 4;16:1411320. doi: 10.3389/fnagi.2024.1411320. PMID: 38894850; PMCID: PMC11185263. 2: Wang D, Ling Y, Harris K, Schulz PE, Jiang X, Kim Y. Characterizing Treatment Non-responders vs. Responders in Completed Alzheimer's Disease Clinical Trials. medRxiv [Preprint]. 2023 Oct 30:2023.10.27.23297685. doi: 10.1101/2023.10.27.23297685. PMID: 37961216; PMCID: PMC10635230. 3: Hakem FT, Fouad YF, Arafa RK. Gamma Secretase as an Important Drug Target for Management of Alzheimer's Disease: A Comprehensive Review. Curr Top Med Chem. 2024;24(2):109-127. doi: 10.2174/0115680266259174231006070637. PMID: 37818580. 4: Vladar EK, Kunimoto K, Rojas-Hernandez LS, Spano JM, Sellers ZM, Joo NS, Cooney RA, Axelrod JD, Milla CE. Notch signaling inactivation by small molecule γ-secretase inhibitors restores the multiciliated cell population in the airway epithelium. Am J Physiol Lung Cell Mol Physiol. 2023 Jun 1;324(6):L771-L782. doi: 10.1152/ajplung.00382.2022. Epub 2023 Apr 11. PMID: 37039381; PMCID: PMC10202488. 5: Saleh MAA, Bloemberg JS, Elassaiss-Schaap J, de Lange ECM. Drug Distribution in Brain and Cerebrospinal Fluids in Relation to IC50 Values in Aging and Alzheimer's Disease, Using the Physiologically Based LeiCNS-PK3.0 Model. Pharm Res. 2022 Jul;39(7):1303-1319. doi: 10.1007/s11095-022-03281-3. Epub 2022 May 23. PMID: 35606598; PMCID: PMC9246802. 6: Jin N, Gureviciene I, Atalay AN, Häkli S, Ziyatdinova S, Tanila H. Preclinical evaluation of drug treatment options for sleep-related epileptiform spiking in Alzheimer's disease. Alzheimers Dement (N Y). 2022 Apr 5;8(1):e12291. doi: 10.1002/trc2.12291. PMID: 35415205; PMCID: PMC8982322. 7: Caldwell AB, Liu Q, Zhang C, Schroth GP, Galasko DR, Rynearson KD, Tanzi RE, Yuan SH, Wagner SL, Subramaniam S. Endotype reversal as a novel strategy for screening drugs targeting familial Alzheimer's disease. Alzheimers Dement. 2022 Nov;18(11):2117-2130. doi: 10.1002/alz.12553. Epub 2022 Jan 27. PMID: 35084109; PMCID: PMC9787711. 8: Nie P, Kalidindi T, Nagle VL, Wu X, Li T, Liao GP, Frost G, Henry KE, Punzalan B, Carter LM, Lewis JS, Pillarsetty NVK, Li YM. Imaging of Cancer γ-Secretase Activity Using an Inhibitor-Based PET Probe. Clin Cancer Res. 2021 Nov 15;27(22):6145-6155. doi: 10.1158/1078-0432.CCR-21-0940. Epub 2021 Sep 2. PMID: 34475100; PMCID: PMC8610083. 9: Madrasi K, Das R, Mohmmadabdul H, Lin L, Hyman BT, Lauffenburger DA, Albers MW, Rissman RA, Burke JM, Apgar JF, Wille L, Gruenbaum L, Hua F. Systematic in silico analysis of clinically tested drugs for reducing amyloid-beta plaque accumulation in Alzheimer's disease. Alzheimers Dement. 2021 Sep;17(9):1487-1498. doi: 10.1002/alz.12312. Epub 2021 May 2. PMID: 33938131; PMCID: PMC8478725. 10: Svedružić ŽM, Vrbnjak K, Martinović M, Miletić V. Structural Analysis of the Simultaneous Activation and Inhibition of γ-Secretase Activity in the Development of Drugs for Alzheimer's Disease. Pharmaceutics. 2021 Apr 8;13(4):514. doi: 10.3390/pharmaceutics13040514. PMID: 33917979; PMCID: PMC8068388. 11: Bernstein OM, Grill JD, Gillen DL. Recruitment and retention of participant and study partner dyads in two multinational Alzheimer's disease registration trials. Alzheimers Res Ther. 2021 Jan 8;13(1):16. doi: 10.1186/s13195-020-00762-8. PMID: 33419457; PMCID: PMC7791680. 12: Yang G, Zhou R, Guo X, Yan C, Lei J, Shi Y. Structural basis of γ-secretase inhibition and modulation by small molecule drugs. Cell. 2021 Jan 21;184(2):521-533.e14. doi: 10.1016/j.cell.2020.11.049. Epub 2020 Dec 28. PMID: 33373587. 13: Ezzati A, Lipton RB; Alzheimer’s Disease Neuroimaging Initiative. Machine Learning Predictive Models Can Improve Efficacy of Clinical Trials for Alzheimer's Disease. J Alzheimers Dis. 2020;74(1):55-63. doi: 10.3233/JAD-190822. PMID: 31985462; PMCID: PMC7201366. 14: Chothe PP, Wu SP, Ye Z, Hariparsad N. Assessment of Transporter-Mediated and Passive Hepatic Uptake Clearance Using Rifamycin-SV as a Pan-Inhibitor of Active Uptake. Mol Pharm. 2018 Oct 1;15(10):4677-4688. doi: 10.1021/acs.molpharmaceut.8b00654. Epub 2018 Aug 27. PMID: 29996058. 15: Ruthirakuhan MT, Herrmann N, Abraham EH, Chan S, Lanctôt KL. Pharmacological interventions for apathy in Alzheimer's disease. Cochrane Database Syst Rev. 2018 May 4;5(5):CD012197. doi: 10.1002/14651858.CD012197.pub2. PMID: 29727467; PMCID: PMC6494556. 16: Geerts H, Spiros A, Roberts P. Impact of amyloid-beta changes on cognitive outcomes in Alzheimer's disease: analysis of clinical trials using a quantitative systems pharmacology model. Alzheimers Res Ther. 2018 Feb 2;10(1):14. doi: 10.1186/s13195-018-0343-5. PMID: 29394903; PMCID: PMC5797372. 17: 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. 18: 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. 19: Penninkilampi R, Brothers HM, Eslick GD. Pharmacological Agents Targeting γ-Secretase Increase Risk of Cancer and Cognitive Decline in Alzheimer's Disease Patients: A Systematic Review and Meta-Analysis. J Alzheimers Dis. 2016 Jul 6;53(4):1395-404. doi: 10.3233/JAD-160275. PMID: 27392862. 20: Colin J, Allouche A, Chauveau F, Corbier C, Pauron-Gregory L, Lanhers MC, Claudepierre T, Yen FT, Oster T, Malaplate-Armand C. Improved Neuroprotection Provided by Drug Combination in Neurons Exposed to Cell-Derived Soluble Amyloid-β Peptide. J Alzheimers Dis. 2016 May 7;52(3):975-87. doi: 10.3233/JAD-151110. PMID: 27163806. 86950.