Aloxistatin (E-64d)

• CAS: 88321-09-9
• Catalog Number: ACM88321099
• Category: Inhibitors
• Molecular Weight: 342.44
• Molecular Formula: C17H30N2O5
• Description: Aloxistatin (E-64d), is a selective cysteine protease inhibitor or calpain and autophagy inhibitor. E-64d prevents in vitro cerulein- induced trypsinogen activation. E-64d can enter the intact cell and inhibit calpain. E-64d has been shown safe for the treatment of Alzheimer's disease in human. E-64d is potentially useful in the treatment of developmental seizure-induced brain damage both by regulating abnormal zinc signal transduction and through the modulation of altered lipid metabolism via ApoE/clusterin pathway in hippocampus.
• Synonyms: E-64d; E 64d; E64d; E64-d; E64-d; E64 d; ethyl ester Loxistatin; NSC 694281; NSC694281; NSC-694281; EST; EP-453; EP453; EP 453; Aloxistatin
• IUPAC Name: ethyl (2S,3S)-3-(((S)-1-(isopentylamino)-4-methyl-1-oxopentan-2-yl)carbamoyl)oxirane-2-carboxylate
• Canonical SMILES: CCOC([C@@H]1[C@@H](C(N[C@H](C(NCCC(C)C)=O)CC(C)C)=O)O1)=O
• InChI: InChI=1S/C17H30N2O5/c1-6-23-17(22)14-13(24-14)16(21)19-12(9-11(4)5)15(20)18-8-7-10(2)3/h10-14H,6-9H2,1-5H3,(H,18,20)(H,19,21)/t12-,13-,14-/m0/s1
• InChI Key: SRVFFFJZQVENJC-IHRRRGAJSA-N
• Solubility: Soluble in DMSO, not in water
• Appearance: Solid powder
• Shelf Life: >2 years if stored properly
• Storage: Dry, dark and at 0-4 °C for short term (days to weeks) or -20 °C for long term (months to years).
• Biological Target: Aloxistatin (E64d) is a cell-permeable and irreversible broad-spectrum cysteine protease inhibitor. Aloxistatin (E64d) exhibits entry-blocking effect for MERS-CoV.
• Drug Formulation: This drug may be formulated in DMSO
• Elemental Analysis: C, 59.63; H, 8.83; N, 8.18; O, 23.36
• Exact Mass: 342.21547
• HS Tariff Code: 2934.99.9001
• In Vitro Activity: E-64d, a membrane permeant derivative of E-64c, a thiol protease inhibitor (Tamai et al. (1986) J. Pharmacobio-Dyn. 9, 672-677), was tested for ability to inhibit calpain activity in intact platelets. Calpain activity was measured by proteolysis of actin-binding protein and talin, two known substrates of calpain. Incubation of platelets with E-64c (not permeant) or E-64d before lysis prevented proteolysis after lysis. When the platelets were incubated with E-64c or E-64d and then washed to remove the drugs before lysis, only E-64d inhibited proteolysis. When platelets were incubated with E-64c or E-64d and then activated with A23187 plus calcium, a treatment that activates intraplatelet calpain, only E-64d inhibited proteolysis. These results indicate that E-64d can enter the intact cell and inhibit calpain.; Reference: Biochem Biophys Res Commun. 1989 Jan 31;158(2):432-5. https://linkinghub.elsevier.com/retrieve/pii/S0006-291X(89)80065-8
• In Vivo Activity: To evaluate that issue, a cysteine protease inhibitor, E64d, was orally administered to normal guinea pigs or transgenic mice expressing human AβPP, both of which express the human wild-type β-secretase site sequence. In guinea pigs, oral E64d administration caused a dose-dependent reduction of up to 92% in brain, CSF, and plasma of Aβ40 and Aβ42, a reduction of up to 50% in the C-terminal β-secretase fragment (CTFβ), and a 91% reduction in brain cathepsin B activity, but increased brain BACE1 activity by 20%. In transgenic AD mice, oral E64d administration improved memory deficits and reduced brain Aβ40 and Aβ42, amyloid plaque, brain CTFβ, and brain cathepsin B activity, but increased brain BACE1 activity. It's concluded that E64d likely reduces brain Aβ by inhibiting cathepsin B and not BACE1 β-secretase activity and that E64d therefore may have potential for treating AD patients.; Reference: J Alzheimers Dis. 2011;26(2):387-408. https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/21613740/
• Shipping: 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.
• Stock Solution Storage: 0-4 °C for short term (days to weeks), or -20 °C for long term (months).

Synthetic Use

Upstream Synthesis Route 1

• 63734-73-6
• 84851-37-6

• 88321-09-9

Reference: [1] Patent: US2017/166543, 2017, A1, . Location in patent: Paragraph 0056; 0057; 0059; 0072; 0073

Upstream Synthesis Route 2

• 63734-73-6

• 88321-09-9

Reference: [1] Patent: US2017/166543, 2017, A1, . Location in patent: Paragraph 0056; 0059; 0063; 0070; 0071; 0110; 0113

Upstream Synthesis Route 3

• 107-85-7
• 174759-66-1

• 88321-09-9

Reference: [1] Synthesis, 1999, # SPEC. ISS., p. 1500 - 1504

Upstream Synthesis Route 4

• 84851-37-6
• 100464-19-5

• 88321-09-9

Reference: [1]Patent: US2017/166543,2017,A1 .Location in patent: Paragraph 0057

Downstream Synthesis Route 1

• 88321-09-9

• 76684-89-4

Reference: [1]Chinese Chemical Letters,2013,vol. 24,p. 715 - 718
[2]Journal of Medicinal Chemistry,1996,vol. 39,p. 3357 - 3366
[3]Journal of Medicinal Chemistry,1992,vol. 35,p. 2048 - 2054

* For details of the synthesis route, please refer to the original source to ensure accuracy.