Aloxistatin

Aloxistatin
Clinical data
ATC code	none;
Legal status
Legal status	US: Investigational drug ;
Identifiers
	IUPAC name ethyl (2S,3S)-3-[[(2S)-4-methyl-1-(3-methylbutylamino)-1-oxopentan-2-yl]carbamoyl]oxirane-2-carboxylate;
CAS Number	88321-09-9;
PubChem CID	65663;
ChemSpider	59098;
UNII	L5W337AOUR;
ChEBI	CHEBI:101381;
ChEMBL	ChEMBL63440;
CompTox Dashboard (EPA)	DTXSID00904150 ;
ECHA InfoCard	100.163.683
Chemical and physical data
Formula	C17H30N2O5
Molar mass	342.4 g·mol−1
3D model (JSmol)	Interactive image;
	SMILES CCOC(=O)[C@@H]1[C@H](O1)C(=O)N[C@@H](CC(C)C)C(=O)NCCC(C)C;
	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; Key:SRVFFFJZQVENJC-IHRRRGAJSA-N;

Aloxistatin (loxistatin, E-64d, EST) is a drug which acts as a cysteine protease inhibitor and has anticoagulant effects. It is a synthetic analogue of E-64, a natural product derived from fungi.[1][2][3] It was researched for the treatment of muscular dystrophy but was not successful in human clinical trials,[4] though it has continued to be investigated for treatment of spinal cord injury, stroke and Alzheimer's disease.[5][6][7][8][9] It also shows antiviral effects.[10][11]

References

Tamai M, Matsumoto K, Omura S, Koyama I, Ozawa Y, Hanada K (August 1986). "In vitro and in vivo inhibition of cysteine proteinases by EST, a new analog of E-64". Journal of Pharmacobio-Dynamics. 9 (8): 672–7. doi:10.1248/bpb1978.9.672. PMID 3023601.
Tamai M, Yokoo C, Murata M, Oguma K, Sota K, Sato E, Kanaoka Y (March 1987). "Efficient synthetic method for ethyl (+)-(2S,3S)-3-[(S)-3-methyl- 1-(3-methylbutylcarbamoyl)butylcarbamoyl]-2-oxiranecarb oxylate (EST), a new inhibitor of cysteine proteinases". Chemical & Pharmaceutical Bulletin. 35 (3): 1098–104. PMID 3301019.
Zhang X, Yang X, Wang H, Li S, Guo K, Jiang D, et al. (August 2017). "Design, Synthesis, and Structure-Activity Relationship Study of Epoxysuccinyl-Peptide Derivatives as Cathepsin B Inhibitors". Biological & Pharmaceutical Bulletin. 40 (8): 1240–1246. doi:10.1248/bpb.b17-00075. PMID 28502922.
Satoyoshi E (July 1992). "Therapeutic trials on progressive muscular dystrophy". Internal Medicine. 31 (7): 841–6. doi:10.2169/internalmedicine.31.841. PMID 1450492.
Ray SK, Matzelle DD, Wilford GG, Hogan EL, Banik NL (June 2001). "Cell death in spinal cord injury (SCI) requires de novo protein synthesis. Calpain inhibitor E-64-d provides neuroprotection in SCI lesion and penumbra". Annals of the New York Academy of Sciences. 939: 436–49. doi:10.1111/j.1749-6632.2001.tb03655.x. PMID 11462799.
Tsubokawa T, Yamaguchi-Okada M, Calvert JW, Solaroglu I, Shimamura N, Yata K, Zhang JH (September 2006). "Neurovascular and neuronal protection by E64d after focal cerebral ischemia in rats". Journal of Neuroscience Research. 84 (4): 832–40. doi:10.1002/jnr.20977. PMID 16802320.
Trinchese F, Fa' M, Liu S, Zhang H, Hidalgo A, Schmidt SD, et al. (August 2008). "Inhibition of calpains improves memory and synaptic transmission in a mouse model of Alzheimer disease". The Journal of Clinical Investigation. 118 (8): 2796–807. doi:10.1172/JCI34254. PMID 18596919.
Hook G, Hook V, Kindy M. "The cysteine protease inhibitor, E64d, reduces brain amyloid-β and improves memory deficits in Alzheimer's disease animal models by inhibiting cathepsin B, but not BACE1, β-secretase activity". Journal of Alzheimer's Disease. 26 (2): 387–408. doi:10.3233/JAD-2011-110101. PMID 21613740.
Hook G, Yu J, Toneff T, Kindy M, Hook V. "Brain pyroglutamate amyloid-β is produced by cathepsin B and is reduced by the cysteine protease inhibitor E64d, representing a potential Alzheimer's disease therapeutic". Journal of Alzheimer's Disease. 41 (1): 129–49. doi:10.3233/JAD-131370. PMC 4059604. PMID 24595198.
Kim JC, Spence RA, Currier PF, Lu X, Denison MR (April 1995). "Coronavirus protein processing and RNA synthesis is inhibited by the cysteine proteinase inhibitor E64d". Virology. 208 (1): 1–8. doi:10.1006/viro.1995.1123. PMID 11831690.
Kumar P, Nachagari D, Fields C, Franks J, Albritton LM (October 2007). "Host cell cathepsins potentiate Moloney murine leukemia virus infection". Journal of Virology. 81 (19): 10506–14. doi:10.1128/JVI.02853-06. PMID 17634228.

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[1] Tamai M, Matsumoto K, Omura S, Koyama I, Ozawa Y, Hanada K (August 1986). "In vitro and in vivo inhibition of cysteine proteinases by EST, a new analog of E-64". Journal of Pharmacobio-Dynamics. 9 (8): 672–7. doi:10.1248/bpb1978.9.672. PMID 3023601.

[2] Tamai M, Yokoo C, Murata M, Oguma K, Sota K, Sato E, Kanaoka Y (March 1987). "Efficient synthetic method for ethyl (+)-(2S,3S)-3-[(S)-3-methyl- 1-(3-methylbutylcarbamoyl)butylcarbamoyl]-2-oxiranecarb oxylate (EST), a new inhibitor of cysteine proteinases". Chemical & Pharmaceutical Bulletin. 35 (3): 1098–104. PMID 3301019.

[3] Zhang X, Yang X, Wang H, Li S, Guo K, Jiang D, et al. (August 2017). "Design, Synthesis, and Structure-Activity Relationship Study of Epoxysuccinyl-Peptide Derivatives as Cathepsin B Inhibitors". Biological & Pharmaceutical Bulletin. 40 (8): 1240–1246. doi:10.1248/bpb.b17-00075. PMID 28502922.

[4] Satoyoshi E (July 1992). "Therapeutic trials on progressive muscular dystrophy". Internal Medicine. 31 (7): 841–6. doi:10.2169/internalmedicine.31.841. PMID 1450492.

[5] Ray SK, Matzelle DD, Wilford GG, Hogan EL, Banik NL (June 2001). "Cell death in spinal cord injury (SCI) requires de novo protein synthesis. Calpain inhibitor E-64-d provides neuroprotection in SCI lesion and penumbra". Annals of the New York Academy of Sciences. 939: 436–49. doi:10.1111/j.1749-6632.2001.tb03655.x. PMID 11462799.

[6] Tsubokawa T, Yamaguchi-Okada M, Calvert JW, Solaroglu I, Shimamura N, Yata K, Zhang JH (September 2006). "Neurovascular and neuronal protection by E64d after focal cerebral ischemia in rats". Journal of Neuroscience Research. 84 (4): 832–40. doi:10.1002/jnr.20977. PMID 16802320.

[7] Trinchese F, Fa' M, Liu S, Zhang H, Hidalgo A, Schmidt SD, et al. (August 2008). "Inhibition of calpains improves memory and synaptic transmission in a mouse model of Alzheimer disease". The Journal of Clinical Investigation. 118 (8): 2796–807. doi:10.1172/JCI34254. PMID 18596919.

[8] Hook G, Hook V, Kindy M. "The cysteine protease inhibitor, E64d, reduces brain amyloid-β and improves memory deficits in Alzheimer's disease animal models by inhibiting cathepsin B, but not BACE1, β-secretase activity". Journal of Alzheimer's Disease. 26 (2): 387–408. doi:10.3233/JAD-2011-110101. PMID 21613740.

[9] Hook G, Yu J, Toneff T, Kindy M, Hook V. "Brain pyroglutamate amyloid-β is produced by cathepsin B and is reduced by the cysteine protease inhibitor E64d, representing a potential Alzheimer's disease therapeutic". Journal of Alzheimer's Disease. 41 (1): 129–49. doi:10.3233/JAD-131370. PMC 4059604. PMID 24595198.

[10] Kim JC, Spence RA, Currier PF, Lu X, Denison MR (April 1995). "Coronavirus protein processing and RNA synthesis is inhibited by the cysteine proteinase inhibitor E64d". Virology. 208 (1): 1–8. doi:10.1006/viro.1995.1123. PMID 11831690.

[11] Kumar P, Nachagari D, Fields C, Franks J, Albritton LM (October 2007). "Host cell cathepsins potentiate Moloney murine leukemia virus infection". Journal of Virology. 81 (19): 10506–14. doi:10.1128/JVI.02853-06. PMID 17634228.