Emricasan
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MedKoo CAT#: 510230

CAS#: 254750-02-2

Description: Emricasan, also known as IDN 6556 and PF 03491390, is a first-in-class caspase inhibitor in clinical trials for the treatment of liver diseases. Emricasan (IDN-6556) decreases liver injury and fibrosis in a murine model of non-alcoholic steatohepatitis. IDN6556 facilitates marginal mass islet engraftment in a porcine islet autotransplant model. Oral IDN-6556 may lower aminotransferase activity in patients with chronic hepatitis C. Orally-administered PF-03491390 is retained in the liver for prolonged periods with low systemic exposure, exerting a hepatoprotective effect against alpha-fas-induced liver injury in a mouse model.


Chemical Structure

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Emricasan
CAS# 254750-02-2

Theoretical Analysis

MedKoo Cat#: 510230
Name: Emricasan
CAS#: 254750-02-2
Chemical Formula: C26H27F4N3O7
Exact Mass: 569.17851
Molecular Weight: 569.51
Elemental Analysis: C, 54.83; H, 4.78; F, 13.34; N, 7.38; O, 19.66

Price and Availability

Size Price Availability Quantity
5.0mg USD 80.0 Ready to ship
10.0mg USD 150.0 Ready to ship
25.0mg USD 250.0 Ready to ship
50.0mg USD 450.0 Ready to ship
100.0mg USD 750.0 Ready to ship
200.0mg USD 1250.0 Ready to ship
500.0mg USD 2450.0 Ready to ship
1.0g USD 3650.0 Ready to ship
2.0g USD 5950.0 2 Weeks
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Synonym: IDN-6556; IDN6556; IDN 6556; PF 03491390; PF-03491390; PF03491390; Emricasan.

IUPAC/Chemical Name: (S)-3-((S)-2-(2-((2-(tert-butyl)phenyl)amino)-2-oxoacetamido)propanamido)-4-oxo-5-(2,3,5,6-tetrafluorophenoxy)pentanoic acid

InChi Key: SCVHJVCATBPIHN-SJCJKPOMSA-N

InChi Code: InChI=1S/C26H27F4N3O7/c1-12(31-24(38)25(39)32-16-8-6-5-7-13(16)26(2,3)4)23(37)33-17(10-19(35)36)18(34)11-40-22-20(29)14(27)9-15(28)21(22)30/h5-9,12,17H,10-11H2,1-4H3,(H,31,38)(H,32,39)(H,33,37)(H,35,36)/t12-,17-/m0/s1

SMILES Code: O=C(O)C[C@H](NC([C@H](C)NC(C(NC1=CC=CC=C1C(C)(C)C)=O)=O)=O)C(COC2=C(F)C(F)=CC(F)=C2F)=O

Appearance: white 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: >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: 2934.99.9001

Biological target: Emricasan (PF 03491390) is an orally active and irreversible pan-caspase inhibitor.
In vitro activity: Figure 7 shows that human cirrhotic hepatocytes cultured in vitro and treated with emricasan exhibit a marked amelioration in their phenotype when compared with vehicle‐treated cells, with improved expression of HNF4α, abcc3 and slc22a1, and higher albumin and urea synthesis, without signs of hepatotoxicity. The number of hepatocytes at the end of the experiment were not different between groups, as indicated by the amount of RNA obtained in each experimental condition. Interestingly, the beneficial effects of the drug were not observed in hepatocytes undergoing spontaneous de‐differentiation due to culture in conventional methods (data not shown). References: Hepatol Commun. 2019 Jul; 3(7): 987–1000. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6601324/
In vivo activity: Mice fed a HFD diet demonstrate a five-fold increase in hepatocyte apoptosis by the TUNEL assay and a 1.5-fold and 1.3-fold increase in caspase-3 and-8 activities respectively; this increase in apoptosis was substantially attenuated in mice fed a HFD treated with Emricasan (HFD-Em). Likewise, liver injury and inflammation were reduced in mice fed HFD-Em as compare to HFD by measuring serum aspartate aminotransferase and alanine aminotransferase levels, NAS histological score and IL 1-β, TNF-α, monocyte chemoattractant protein (MCP-1) and C-X-C chemokine ligand-2 (CXCL2) quantitative reverse-transcription polymerase chain reaction (qPCR). These differences could not be attributed to differences in hepatic steatosis as liver triglycerides content were similar in both HFD groups. Hepatic fibrosis was reduced by Emricasan in HFD animals by decreasing αSMA (a marker for hepatic stellate cell activation), fibrosis score, Sirius red staining, hydroxyproline liver content and profibrogenic cytokines by qPCR. Reference: Liver Int. 2015 Mar;35(3):953-66. https://onlinelibrary.wiley.com/doi/abs/10.1111/liv.12570

Solubility Data

Solvent Max Conc. mg/mL Max Conc. mM
Solubility
DMSO 42.0 73.75
Ethanol 100.0 175.59

Preparing Stock Solutions

The following data is based on the product molecular weight 569.51 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
In vitro protocol: 1. Gracia-Sancho J, Manicardi N, Ortega-Ribera M, Maeso-Díaz R, Guixé-Muntet S, Fernández-Iglesias A, Hide D, García-Calderó H, Boyer-Díaz Z, Contreras PC, Spada A, Bosch J. Emricasan Ameliorates Portal Hypertension and Liver Fibrosis in Cirrhotic Rats Through a Hepatocyte-Mediated Paracrine Mechanism. Hepatol Commun. 2019 Apr 22;3(7):987-1000. doi: 10.1002/hep4.1360. PMID: 31304452; PMCID: PMC6601324. 2. Xu M, Lee EM, Wen Z, Cheng Y, Huang WK, Qian X, Tcw J, Kouznetsova J, Ogden SC, Hammack C, Jacob F, Nguyen HN, Itkin M, Hanna C, Shinn P, Allen C, Michael SG, Simeonov A, Huang W, Christian KM, Goate A, Brennand KJ, Huang R, Xia M, Ming GL, Zheng W, Song H, Tang H. Identification of small-molecule inhibitors of Zika virus infection and induced neural cell death via a drug repurposing screen. Nat Med. 2016 Oct;22(10):1101-1107. doi: 10.1038/nm.4184. Epub 2016 Aug 29. PMID: 27571349; PMCID: PMC5386783.
In vivo protocol: 1. Barreyro FJ, Holod S, Finocchietto PV, Camino AM, Aquino JB, Avagnina A, Carreras MC, Poderoso JJ, Gores GJ. The pan-caspase inhibitor Emricasan (IDN-6556) decreases liver injury and fibrosis in a murine model of non-alcoholic steatohepatitis. Liver Int. 2015 Mar;35(3):953-66. doi: 10.1111/liv.12570. Epub 2014 Jun 6. PMID: 24750664. 2. Hoglen NC, Chen LS, Fisher CD, Hirakawa BP, Groessl T, Contreras PC. Characterization of IDN-6556 (3-[2-(2-tert-butyl-phenylaminooxalyl)-amino]-propionylamino]-4-oxo-5-(2,3,5,6-tetrafluoro-phenoxy)-pentanoic acid): a liver-targeted caspase inhibitor. J Pharmacol Exp Ther. 2004 May;309(2):634-40. doi: 10.1124/jpet.103.062034. Epub 2004 Jan 23. PMID: 14742742.

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Garcia LR, Tenev T, Newman R, Haich RO, Liccardi G, John SW, Annibaldi A, Yu L, Pardo M, Young SN, Fitzgibbon C, Fernando W, Guppy N, Kim H, Liang LY, Lucet IS, Kueh A, Roxanis I, Gazinska P, Sims M, Smyth T, Ward G, Bertin J, Beal AM, Geddes B, Choudhary JS, Murphy JM, Aurelia Ball K, Upton JW, Meier P. Ubiquitylation of MLKL at lysine 219 positively regulates necroptosis-induced tissue injury and pathogen clearance. Nat Commun. 2021 Jun 7;12(1):3364. doi: 10.1038/s41467-021-23474-5. PMID: 34099649; PMCID: PMC8184782.

1: Rotman Y, Sanyal AJ. Current and upcoming pharmacotherapy for non-alcoholic fatty liver disease. Gut. 2016 Sep 19. pii: gutjnl-2016-312431. doi: 10.1136/gutjnl-2016-312431. [Epub ahead of print] Review. PubMed PMID: 27646933.

2: Xu M, Lee EM, Wen Z, Cheng Y, Huang WK, Qian X, Tcw J, Kouznetsova J, Ogden SC, Hammack C, Jacob F, Nguyen HN, Itkin M, Hanna C, Shinn P, Allen C, Michael SG, Simeonov A, Huang W, Christian KM, Goate A, Brennand KJ, Huang R, Xia M, Ming GL, Zheng W, Song H, Tang H. Identification of small-molecule inhibitors of Zika virus infection and induced neural cell death via a drug repurposing screen. Nat Med. 2016 Oct;22(10):1101-1107. doi: 10.1038/nm.4184. PubMed PMID: 27571349.

3: Brumatti G, Ma C, Lalaoui N, Nguyen NY, Navarro M, Tanzer MC, Richmond J, Ghisi M, Salmon JM, Silke N, Pomilio G, Glaser SP, de Valle E, Gugasyan R, Gurthridge MA, Condon SM, Johnstone RW, Lock R, Salvesen G, Wei A, Vaux DL, Ekert PG, Silke J. The caspase-8 inhibitor emricasan combines with the SMAC mimetic birinapant to induce necroptosis and treat acute myeloid leukemia. Sci Transl Med. 2016 May 18;8(339):339ra69. doi: 10.1126/scitranslmed.aad3099. PubMed PMID: 27194727.

4: Elbekai RH, Paranjpe MG, Contreras PC, Spada A. Carcinogenicity assessment of the pan-caspase inhibitor, emricasan, in Tg.rasH2 mice. Regul Toxicol Pharmacol. 2015 Jul;72(2):169-78. doi: 10.1016/j.yrtph.2015.04.007. Epub 2015 Apr 17. PubMed PMID: 25896096.

5: Barreyro FJ, Holod S, Finocchietto PV, Camino AM, Aquino JB, Avagnina A, Carreras MC, Poderoso JJ, Gores GJ. The pan-caspase inhibitor Emricasan (IDN-6556) decreases liver injury and fibrosis in a murine model of non-alcoholic steatohepatitis. Liver Int. 2015 Mar;35(3):953-66. doi: 10.1111/liv.12570. Epub 2014 Jun 6. PubMed PMID: 24750664.

6: Haddad JJ. Current opinion on 3-[2-[(2-tert-butyl-phenylaminooxalyl)-amino]-propionylamino]- 4-oxo-5-(2,3,5,6-tetrafluoro-phenoxy)-pentanoic acid, an investigational drug targeting caspases and caspase-like proteases: the clinical trials in sight and recent anti-inflammatory advances. Recent Pat Inflamm Allergy Drug Discov. 2013 Sep;7(3):229-58. Review. PubMed PMID: 23859695.

7: McCall MD, Maciver AM, Kin T, Emamaullee J, Pawlick R, Edgar R, Shapiro AM. Caspase inhibitor IDN6556 facilitates marginal mass islet engraftment in a porcine islet autotransplant model. Transplantation. 2012 Jul 15;94(1):30-5. doi: 10.1097/TP.0b013e318257745d. PubMed PMID: 22706322.

8: McCall M, Toso C, Emamaullee J, Pawlick R, Edgar R, Davis J, Maciver A, Kin T, Arch R, Shapiro AM. The caspase inhibitor IDN-6556 (PF3491390) improves marginal mass engraftment after islet transplantation in mice. Surgery. 2011 Jul;150(1):48-55. doi: 10.1016/j.surg.2011.02.023. Epub 2011 May 18. PubMed PMID: 21596412.

9: Shiffman ML, Pockros P, McHutchison JG, Schiff ER, Morris M, Burgess G. Clinical trial: the efficacy and safety of oral PF-03491390, a pancaspase inhibitor - a randomized placebo-controlled study in patients with chronic hepatitis C. Aliment Pharmacol Ther. 2010 May;31(9):969-78. doi: 10.1111/j.1365-2036.2010.04264.x. Epub 2010 Feb 16. PubMed PMID: 20163376.

10: Pockros PJ. Antifibrotics for chronic hepatitis C. Clin Liver Dis. 2009 Aug;13(3):365-73. doi: 10.1016/j.cld.2009.05.005. Review. PubMed PMID: 19628154.

11: Fischer U, Janssen K, Schulze-Osthoff K. Does caspase inhibition promote clonogenic tumor growth? Cell Cycle. 2007 Dec 15;6(24):3048-53. Epub 2007 Oct 2. Review. PubMed PMID: 18073530.

12: Ueno Y, Ohmi T, Yamamoto M, Kato N, Moriguchi Y, Kojima M, Shimozono R, Suzuki S, Matsuura T, Eda H. Orally-administered caspase inhibitor PF-03491390 is retained in the liver for prolonged periods with low systemic exposure, exerting a hepatoprotective effect against alpha-fas-induced liver injury in a mouse model. J Pharmacol Sci. 2007 Oct;105(2):201-5. Epub 2007 Oct 6. PubMed PMID: 17928737.

13: Pockros PJ, Schiff ER, Shiffman ML, McHutchison JG, Gish RG, Afdhal NH, Makhviladze M, Huyghe M, Hecht D, Oltersdorf T, Shapiro DA. Oral IDN-6556, an antiapoptotic caspase inhibitor, may lower aminotransferase activity in patients with chronic hepatitis C. Hepatology. 2007 Aug;46(2):324-9. PubMed PMID: 17654603.

14: Georgiev P, Clavien PA, Gores GJ. Liver graft protection by antiapoptotic drugs: a step further. Liver Transpl. 2007 Mar;13(3):318-20. PubMed PMID: 17318874.

15: Hoglen NC, Anselmo DM, Katori M, Kaldas M, Shen XD, Valentino KL, Lassman C, Busuttil RW, Kupiec-Weglinski JW, Farmer DG. A caspase inhibitor, IDN-6556, ameliorates early hepatic injury in an ex vivo rat model of warm and cold ischemia. Liver Transpl. 2007 Mar;13(3):361-6. PubMed PMID: 17318854.

16: Baskin-Bey ES, Washburn K, Feng S, Oltersdorf T, Shapiro D, Huyghe M, Burgart L, Garrity-Park M, van Vilsteren FG, Oliver LK, Rosen CB, Gores GJ. Clinical Trial of the Pan-Caspase Inhibitor, IDN-6556, in Human Liver Preservation Injury. Am J Transplant. 2007 Jan;7(1):218-25. PubMed PMID: 17227570.

17: Davis GL. New therapies: oral inhibitors and immune modulators. Clin Liver Dis. 2006 Nov;10(4):867-80. Review. PubMed PMID: 17164122.

18: Leung-Toung R, Zhao Y, Li W, Tam TF, Karimian K, Spino M. Thiol proteases: inhibitors and potential therapeutic targets. Curr Med Chem. 2006;13(5):547-81. Review. PubMed PMID: 16515521.

19: Linton SD, Aja T, Armstrong RA, Bai X, Chen LS, Chen N, Ching B, Contreras P, Diaz JL, Fisher CD, Fritz LC, Gladstone P, Groessl T, Gu X, Herrmann J, Hirakawa BP, Hoglen NC, Jahangiri KG, Kalish VJ, Karanewsky DS, Kodandapani L, Krebs J, McQuiston J, Meduna SP, Nalley K, Robinson ED, Sayers RO, Sebring K, Spada AP, Ternansky RJ, Tomaselli KJ, Ullman BR, Valentino KL, Weeks S, Winn D, Wu JC, Yeo P, Zhang CZ. First-in-class pan caspase inhibitor developed for the treatment of liver disease. J Med Chem. 2005 Nov 3;48(22):6779-82. PubMed PMID: 16250635.

20: Quadri SM, Segall L, de Perrot M, Han B, Edwards V, Jones N, Waddell TK, Liu M, Keshavjee S. Caspase inhibition improves ischemia-reperfusion injury after lung transplantation. Am J Transplant. 2005 Feb;5(2):292-9. PubMed PMID: 15643988.



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