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Chemical Compound Review

Freedox     (8S,10R,13S,14S,16R,17S)-17- [2-[4-(2,6...

Synonyms: Freedox (TN), AC1L2XOW, U-74006F, D01930, U74006F, ...
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Disease relevance of U 74006


High impact information on U 74006

  • The lazaroid compound U74006F is a potent inhibitor of lipid peroxidation, and this study was designed to evaluate the efficacy of this compound in preventing cold ischemia-reperfusion damage in three different models: pig endothelial cells in culture, ex vivo isolated pig liver perfusion and orthotopic transplantation of syngeneic rat livers [1].
  • The addition of U74006F to University of Wisconsin preservation solution significantly prolonged endothelial cell viability after 48 and 72 hr of cold ischemia and reoxygenation (p < 0.01) [1].
  • Treatment with either 100 microM U-74006F or 1 microM U-101033E resulted in a right-hand shift (protection) in the peroxynitrite toxicity curve [6].
  • Vehicle-treated animals exposed to 15 min of ischemia sustained 60 +/- 35% (n = 16) CA1 pyramidal cell necrosis whereas U74006F-treated animals lost 61 +/- 30% (3 mg/kg, n = 9), 42 +/- 35% (10 mg/kg, n = 15), 62 +/- 28% (5 x 10 mg/kg, n = 10), and 74 +/- 30% (8 x 10 mg/kg, n = 10) of CA1 pyramidal cells [7].
  • For animals suffering 5 min of transient forebrain ischemia, vehicle-treated rats lost 19 +/- 26% (n = 14), whereas U74006F-treated (8 x 10 mg/kg) animals lost 36 +/- 39% (n = 15) of CA1 neurons [7].

Chemical compound and disease context of U 74006

  • We tested the hypothesis that when acidosis is augmented by hyperglycemia, pretreatment with the 21-aminosteroid tirilazad mesylate (U74006F), a potent inhibitor of lipid peroxidation in vitro, improves early cerebral metabolic recovery [8].
  • We designed this study to determine whether the aminosteroid U74006F, a putative inhibitor of lipid peroxidation, mitigates cerebral multifocal hypoperfusion after cardiac arrest [5].
  • In contrast, the same doses of U74006F (1.0, 3.0, and 10 mg/kg) that attenuated posttraumatic ischemia also significantly reduced the depletion of cord vitamin E. The lowest U74006F dosage (0.3 mg/kg), which failed to affect posttraumatic ischemia development, also had no effect on spinal cord vitamin E content.(ABSTRACT TRUNCATED AT 250 WORDS)[9]
  • Only one (5.2%) of 19 rats receiving high-dose U74006F (10 mg/kg) died within 72 hours after ischemia, compared with five deaths (29.4%) in 17 rats receiving citrate vehicle alone (p = 0.060) [10].
  • It is hypothesized that reperfusion injury accompanies renal ischemia, and postischemic administration of one of these steroids, U74006F, will reduce renal damage in a rodent model, as assessed by renal function (plasma creatinine), histologic evidence of renal injury, and animal survival during a 72-hour interval [10].

Biological context of U 74006


Anatomical context of U 74006


Associations of U 74006 with other chemical compounds


Gene context of U 74006

  • Their IC(50) ranged from 10(-3) M to 10(-6) M, with 21-amino steroids (U74500A and U74006F) showing a greater selectivity and potency for MAO-A [21].
  • U78517F is a novel inhibitor of iron-catalyzed lipid peroxidation that combines the tetramethylchroman antioxidant ring portion of alpha-tocopherol with the amine of the previously described 21-aminosteroids (e.g., U74006F) [19].
  • Antioxidant lazaroid U-74006F improves renal function and reduces the expression of cytokines, inducible nitric oxide synthase, and MHC antigens in a syngeneic renal transplant model. Partial support for the response-to-injury hypothesis [22].
  • In conclusion, survival of TH-positive neurons is enhanced by U-74006F, which is readily available for clinical use and thus could be employed to enhance graft survival when transplanting patients suffering from Parkinson's disease [23].
  • U74006F-treated animals had significantly reduced MPO activity (60% lower) when compared with vehicle-treated animals at the end of the second and third weeks [24].

Analytical, diagnostic and therapeutic context of U 74006

  • Although bile production was similar in the U74006F-treated and control groups, significant decreases of AST and ALT levels (p < 0.01) in the perfusate of the livers from treated donors were observed [1].
  • A treatment group (n = 5) received U74006F starting with reperfusion (1.5 mg/kg i.a. plus 1.5 mg/kg i.v.) and three additional (graded) doses over 4 hours (total dose 4.5, 7.5, or 14.5 mg/kg) [5].
  • Male Mongolian gerbils received two intraperitoneal injections of either vehicle or U74006F (3 or 10 mg/kg), the first injection 10 minutes before and the second injection at the end of the 3-hour ischemic episode [25].
  • One of these, U74006F or tirilazed mesylate, has been shown to be effective in animal models of brain and spinal cord injury and is currently undergoing phase II clinical trials [26].
  • Pretreatment of 0.3 microM U-74006F during dissection combined with intraocular injections of U-74006F after grafting, on the other hand, resulted in a dose-dependent enhancement of survival of TH-positive neurons [23].


  1. Protective effect of the lazaroid U74006F in cold ischemia-reperfusion injury of the liver. Cosenza, C.A., Cramer, D.V., Cunneen, S.A., Tuso, P.J., Wang, H.K., Makowka, L. Hepatology (1994) [Pubmed]
  2. Effect of U74006F on forebrain ischemia in rats. Lesiuk, H., Sutherland, G., Peeling, J., Butler, K., Saunders, J. Stroke (1991) [Pubmed]
  3. Pretreatment with U74006F improves neurologic outcome following complete cerebral ischemia in dogs. Perkins, W.J., Milde, L.N., Milde, J.H., Michenfelder, J.D. Stroke (1991) [Pubmed]
  4. Effect of high-dose methylprednisolone and U74006F on eicosanoid synthesis after subarachnoid hemorrhage in rats. Gaetani, P., Marzatico, F., Lombardi, D., Adinolfi, D., Rodriguez y Baena, R. Stroke (1991) [Pubmed]
  5. Effects of U74006F on multifocal cerebral blood flow and metabolism after cardiac arrest in dogs. Sterz, F., Safar, P., Johnson, D.W., Oku, K., Tisherman, S.A. Stroke (1991) [Pubmed]
  6. Effects of lazaroids and a peroxynitrite scavenger in a cell model of peroxynitrite toxicity. Fici, G.J., Althaus, J.S., VonVoigtlander, P.F. Free Radic. Biol. Med. (1997) [Pubmed]
  7. Failure of the lipid peroxidation inhibitor, U74006F, to prevent postischemic selective neuronal injury. Buchan, A.M., Bruederlin, B., Heinicke, E., Li, H. J. Cereb. Blood Flow Metab. (1992) [Pubmed]
  8. Tirilazad pretreatment improves early cerebral metabolic and blood flow recovery from hyperglycemic ischemia. Maruki, Y., Koehler, R.C., Kirsch, J.R., Blizzard, K.K., Traystman, R.J. J. Cereb. Blood Flow Metab. (1995) [Pubmed]
  9. Correlation between attenuation of posttraumatic spinal cord ischemia and preservation of tissue vitamin E by the 21-aminosteroid U74006F: evidence for an in vivo antioxidant mechanism. Hall, E.D., Yonkers, P.A., Horan, K.L., Braughler, J.M. J. Neurotrauma (1989) [Pubmed]
  10. Attenuation of renal reperfusion injury in rats by the 21-aminosteroid U74006F. Stanley, J.J., Goldblum, J.R., Frank, T.S., Zelenock, G.B., D'Alecy, L.G. J. Vasc. Surg. (1993) [Pubmed]
  11. Attenuation of postischemic cerebral hypoperfusion by the 21-aminosteroid U74006F. Hall, E.D., Yonkers, P.A. Stroke (1988) [Pubmed]
  12. Effect of the 21-aminosteroid tirilazad on cerebral pH and somatosensory evoked potentials after incomplete ischemia. Maruki, Y., Koehler, R.C., Kirsch, J.R., Blizzard, K.K., Traystman, R.J. Stroke (1993) [Pubmed]
  13. Protective effect of a 21-aminosteroid on the blood-brain barrier following subarachnoid hemorrhage in rats. Zuccarello, M., Anderson, D.K. Stroke (1989) [Pubmed]
  14. The 21-aminosteroid tirilazad mesylate protects against endotoxin shock and acute liver failure in rats. Liu, P., Vonderfecht, S.L., McGuire, G.M., Fisher, M.A., Farhood, A., Jaeschke, H. J. Pharmacol. Exp. Ther. (1994) [Pubmed]
  15. 21-Aminosteroid reduces ion shifts and edema in the rat middle cerebral artery occlusion model of regional ischemia. Young, W., Wojak, J.C., DeCrescito, V. Stroke (1988) [Pubmed]
  16. Evidence for 21-aminosteroid association with the hydrophobic domains of brain microvessel endothelial cells. Audus, K.L., Guillot, F.L., Braughler, J.M. Free Radic. Biol. Med. (1991) [Pubmed]
  17. Effects of tirilazad mesylate on postischemic brain lipid peroxidation and recovery of extracellular calcium in gerbils. Hall, E.D., Pazara, K.E., Braughler, J.M. Stroke (1991) [Pubmed]
  18. 21-aminosteroid and 2-(aminomethyl)chromans inhibition of arachidonic acid-induced lipid peroxidation and permeability enhancement in bovine brain microvessel endothelial cell monolayers. Shi, F., Cavitt, J., Audus, K.L. Free Radic. Biol. Med. (1995) [Pubmed]
  19. Nonsteroidal lazaroid U78517F in models of focal and global ischemia. Hall, E.D., Pazara, K.E., Braughler, J.M., Linseman, K.L., Jacobsen, E.J. Stroke (1990) [Pubmed]
  20. Tirilazad mesylate protects vitamins C and E in brain ischemia-reperfusion injury. Sato, P.H., Hall, E.D. J. Neurochem. (1992) [Pubmed]
  21. Novel bifunctional drugs targeting monoamine oxidase inhibition and iron chelation as an approach to neuroprotection in Parkinson's disease and other neurodegenerative diseases. Youdim, M.B., Fridkin, M., Zheng, H. Journal of neural transmission (Vienna, Austria : 1996) (2004) [Pubmed]
  22. Antioxidant lazaroid U-74006F improves renal function and reduces the expression of cytokines, inducible nitric oxide synthase, and MHC antigens in a syngeneic renal transplant model. Partial support for the response-to-injury hypothesis. Salahudeen, A., Wang, C., McDaniel, O., Lagoo-Denadyalan, S., Bigler, S., Barber, H. Transplantation (1996) [Pubmed]
  23. Tirilazad mesylate increases dopaminergic neuronal survival in the in Oculo grafting model. Björklund, L., Spenger, C., Strömberg, I. Exp. Neurol. (1997) [Pubmed]
  24. The 21-aminosteroid tirilazad mesylate can ameliorate inflammatory bowel disease in rats. Yue, G., Sun, F.F., Dunn, C., Yin, K., Wong, P.Y. J. Pharmacol. Exp. Ther. (1996) [Pubmed]
  25. 21-Aminosteroid lipid peroxidation inhibitor U74006F protects against cerebral ischemia in gerbils. Hall, E.D., Pazara, K.E., Braughler, J.M. Stroke (1988) [Pubmed]
  26. Antioxidant effects in brain and spinal cord injury. Hall, E.D., Braughler, J.M., McCall, J.M. J. Neurotrauma (1992) [Pubmed]
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