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MedKoo Cat#: 500206 | Name: Avagacestat
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Description:

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

Avagacestat, also known as BMS-708163, is an oral GSI designed for selective inhibition of Aβ synthesis currently in development for the treatment of mild to moderate and predementia AD. In addition to the desired effect on Aβ synthesis, GSIs affect Notch processing, which is thought to mediate some toxic adverse effects reported with this drug class.

Chemical Structure

Avagacestat
Avagacestat
CAS#1146699-66-2

Theoretical Analysis

MedKoo Cat#: 500206

Name: Avagacestat

CAS#: 1146699-66-2

Chemical Formula: C20H17ClF4N4O4S

Exact Mass: 520.0595

Molecular Weight: 520.88

Elemental Analysis: C, 46.12; H, 3.29; Cl, 6.81; F, 14.59; N, 10.76; O, 12.29; S, 6.16

Price and Availability

Size Price Availability Quantity
10mg USD 250.00 2 Weeks
50mg USD 650.00 2 Weeks
100mg USD 950.00 2 Weeks
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Related CAS #
No Data
Synonym
Avagacestat; BMS708163; BMS-708163; BMS 708163.
IUPAC/Chemical Name
(R)-2-(4-chloro-N-(2-fluoro-4-(1,2,4-oxadiazol-3-yl)benzyl)phenylsulfonamido)-5,5,5-trifluoropentanamide
InChi Key
MKQKPLQMNCXTJE-VEZQGTPESA-L
InChi Code
InChI=1S/C22H25N6O8P.2Na/c1-2-23-22(29)27-19-16-20(25-11-24-19)28(12-26-16)21-18-17(14(34-21)10-33-37(30,31)32)35-15(36-18)9-8-13-6-4-3-5-7-13;;/h3-9,11-12,14-15,17-18,21H,2,10H2,1H3,(H2,30,31,32)(H2,23,24,25,27,29);;/q;2*+1/p-2/b9-8+;;/t14-,15+,17-,18-,21-;;/m1../s1
SMILES Code
O=C(N)[C@H](N(CC1=CC=C(C2=NOC=N2)C=C1F)S(=O)(C3=CC=C(Cl)C=C3)=O)CCC(F)(F)F
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
>5 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
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Preparing Stock Solutions

The following data is based on the product molecular weight 520.88 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
1: 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. 2: Simutis FJ, Sanderson TP, Pilcher GD, Graziano MJ. Nonclinical Safety Assessment of the γ-Secretase Inhibitor Avagacestat. Toxicol Sci. 2018 Jun 1;163(2):525-542. doi: 10.1093/toxsci/kfy048. PMID: 29529279. 3: Coric V, Salloway S, van Dyck CH, Dubois B, Andreasen N, Brody M, Curtis C, Soininen H, Thein S, Shiovitz T, Pilcher G, Ferris S, Colby S, Kerselaers W, Dockens R, Soares H, Kaplita S, Luo F, Pachai C, Bracoud L, Mintun M, Grill JD, Marek K, Seibyl J, Cedarbaum JM, Albright C, Feldman HH, Berman RM. Targeting Prodromal Alzheimer Disease With Avagacestat: A Randomized Clinical Trial. JAMA Neurol. 2015 Nov;72(11):1324-33. doi: 10.1001/jamaneurol.2015.0607. PMID: 26414022. 4: Albright CF, Dockens RC, Meredith JE Jr, Olson RE, Slemmon R, Lentz KA, Wang JS, Denton RR, Pilcher G, Rhyne PW, Raybon JJ, Barten DM, Burton C, Toyn JH, Sankaranarayanan S, Polson C, Guss V, White R, Simutis F, Sanderson T, Gillman KW, Starrett JE Jr, Bronson J, Sverdlov O, Huang SP, Castaneda L, Feldman H, Coric V, Zaczek R, Macor JE, Houston J, Berman RM, Tong G. Pharmacodynamics of selective inhibition of γ-secretase by avagacestat. J Pharmacol Exp Ther. 2013 Mar;344(3):686-95. doi: 10.1124/jpet.112.199356. Epub 2012 Dec 28. PMID: 23275065. 5: Tong G, Castaneda L, Wang JS, Sverdlov O, Huang SP, Slemmon R, Gu H, Wong O, Li H, Berman RM, Smith C, Albright C, Dockens RC. Effects of single doses of avagacestat (BMS-708163) on cerebrospinal fluid Aβ levels in healthy young men. Clin Drug Investig. 2012 Nov;32(11):761-9. doi: 10.1007/s40261-012-0006-4. PMID: 23018285. 6: Lu L, Zheng X, Wang S, Tang C, Zhang Y, Yao G, Zeng J, Ge S, Wen H, Xu M, Guyatt G, Xu N. Anti-Aβ agents for mild to moderate Alzheimer's disease: systematic review and meta-analysis. J Neurol Neurosurg Psychiatry. 2020 Dec;91(12):1316-1324. doi: 10.1136/jnnp-2020-323497. Epub 2020 Oct 12. PMID: 33046560. 7: Coric V, van Dyck CH, Salloway S, Andreasen N, Brody M, Richter RW, Soininen H, Thein S, Shiovitz T, Pilcher G, Colby S, Rollin L, Dockens R, Pachai C, Portelius E, Andreasson U, Blennow K, Soares H, Albright C, Feldman HH, Berman RM. Safety and tolerability of the γ-secretase inhibitor avagacestat in a phase 2 study of mild to moderate Alzheimer disease. Arch Neurol. 2012 Nov;69(11):1430-40. doi: 10.1001/archneurol.2012.2194. PMID: 22892585. 8: Tong G, Wang JS, Sverdlov O, Huang SP, Slemmon R, Croop R, Castaneda L, Gu H, Wong O, Li H, Berman RM, Smith C, Albright CF, Dockens R. A contrast in safety, pharmacokinetics and pharmacodynamics across age groups after a single 50 mg oral dose of the γ-secretase inhibitor avagacestat. Br J Clin Pharmacol. 2013 Jan;75(1):136-45. doi: 10.1111/j.1365-2125.2012.04339.x. PMID: 22616739; PMCID: PMC3555053. 9: Sivaraman L, Sanderson T. Gamma secretase inhibition: Effects on fertility and embryo-fetal development in rats. Toxicol Appl Pharmacol. 2023 Jun 15;469:116512. doi: 10.1016/j.taap.2023.116512. Epub 2023 Apr 6. PMID: 37030625. 10: Dockens R, Wang JS, Castaneda L, Sverdlov O, Huang SP, Slemmon R, Gu H, Wong O, Li H, Berman RM, Smith C, Albright CF, Tong G. A placebo-controlled, multiple ascending dose study to evaluate the safety, pharmacokinetics and pharmacodynamics of avagacestat (BMS-708163) in healthy young and elderly subjects. Clin Pharmacokinet. 2012 Oct 1;51(10):681-93. doi: 10.1007/s40262-012-0005-x. PMID: 23018531. 11: Tong G, Wang JS, Sverdlov O, Huang SP, Slemmon R, Croop R, Castaneda L, Gu H, Wong O, Li H, Berman RM, Smith C, Albright CF, Dockens RC. Multicenter, randomized, double-blind, placebo-controlled, single-ascending dose study of the oral γ-secretase inhibitor BMS-708163 (Avagacestat): tolerability profile, pharmacokinetic parameters, and pharmacodynamic markers. Clin Ther. 2012 Mar;34(3):654-67. doi: 10.1016/j.clinthera.2012.01.022. Epub 2012 Feb 28. PMID: 22381714. 12: Sogorb-Esteve A, García-Ayllón MS, Llansola M, Felipo V, Blennow K, Sáez- Valero J. Inhibition of γ-Secretase Leads to an Increase in Presenilin-1. Mol Neurobiol. 2018 Jun;55(6):5047-5058. doi: 10.1007/s12035-017-0705-1. Epub 2017 Aug 16. PMID: 28815510; PMCID: PMC5948247. 13: Simutis FJ, Sanderson TP, Pilcher GD, Graziano MJ. Investigations on the Relationship Between Ovarian, Endocrine, and Renal Findings in Nonclinical Safety Studies of the γ-Secretase Inhibitor Avagacestat. Toxicol Sci. 2019 Sep 1;171(1):98-116. doi: 10.1093/toxsci/kfz129. PMID: 31165171. 14: Burrell RC, Easter JA, Cassidy MP, Gillman KW, Olson RE, Bonacorsi SJ. Synthesis of carbon-14 and stable isotope labeled Avagacestat: a novel gamma secretase inhibitor for the treatment of Alzheimer's disease. J Labelled Comp Radiopharm. 2014 Aug;57(10):600-5. doi: 10.1002/jlcr.3224. Epub 2014 Sep 5. PMID: 25196195. 15: 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. 16: Karelina T, Demin O, Nicholas T, Lu Y, Duvvuri S, Barton HA. A Translational Systems Pharmacology Model for Aβ Kinetics in Mouse, Monkey, and Human. CPT Pharmacometrics Syst Pharmacol. 2017 Oct;6(10):666-675. doi: 10.1002/psp4.12211. Epub 2017 Aug 10. PMID: 28571112; PMCID: PMC5658289. 17: Toyn J. What lessons can be learned from failed Alzheimer's disease trials? Expert Rev Clin Pharmacol. 2015 May;8(3):267-9. doi: 10.1586/17512433.2015.1034690. Epub 2015 Apr 10. PMID: 25860157. 18: Hopkins CR. ACS chemical neuroscience molecule spotlight on BMS-708163. ACS Chem Neurosci. 2012 Mar 21;3(3):149-50. doi: 10.1021/cn3000179. PMID: 22860183; PMCID: PMC3369796. 19: Amanatkar HR, Papagiannopoulos B, Grossberg GT. Analysis of recent failures of disease modifying therapies in Alzheimer's disease suggesting a new methodology for future studies. Expert Rev Neurother. 2017 Jan;17(1):7-16. doi: 10.1080/14737175.2016.1194203. Epub 2016 Jun 9. PMID: 27223100. 20: Bansal R, van Baarlen J, Storm G, Prakash J. The interplay of the Notch signaling in hepatic stellate cells and macrophages determines the fate of liver fibrogenesis. Sci Rep. 2015 Dec 14;5:18272. doi: 10.1038/srep18272. PMID: 26658360; PMCID: PMC4677309.

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