59587-09-6Relevant articles and documents
Preclinical Characterization of 3β-(N-Acetyl l -cysteine methyl ester)-2aβ,3-dihydrogaliellalactone (GPA512), a Prodrug of a Direct STAT3 Inhibitor for the Treatment of Prostate Cancer
Escobar, Zilma,Bjartell, Anders,Canesin, Giacomo,Evans-Axelsson, Susan,Sterner, Olov,Hellsten, Rebecka,Johansson, Martin H.
, p. 4551 - 4562 (2016)
The transcription factor STAT3 is a potential target for the treatment of castration-resistant prostate cancer. Galiellalactone (1), a direct inhibitor of STAT3, prevents the transcription of STAT3 regulated genes. In this study we characterized 6 (GPA512, Johansson, M.; Sterner, O. Patent WO 2015/132396 A1, 2015), a prodrug of 1. In vitro studies showed that 6 is rapidly converted to 1 in plasma and is stable in a buffer solution. The pharmacokinetics of 6 following a single oral dose indicated that the prodrug was rapidly absorbed and converted to 1 with a tmax of 15 min. Oral administration of 6 in mice increased the plasma exposure of the active parent compound 20-fold compared to when 1 was dosed orally. 6 treated mice bearing DU145 xenograft tumors had significantly reduced tumor growth compared to untreated mice. The favorable druglike properties and safety profile of 6 warrant further studies of 6 for the treatment of castration-resistant prostate cancer.
COMPOUNDS AND IMPLANTS FOR TREATING OCULAR DISORDERS
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Paragraph 0215, (2021/05/15)
The present disclosure relates to therapeutic compositions and therapies for use in the treatment of diseases and disorders of the eye. The present disclosure relates to curved, multilayer controlled-release ocular implant devices which include the therapeutic compositions of the present disclosure. The present disclosure related to methods for delivery of the therapeutic agents to the eye and the treatment of diseases and disorders of the eye.
Protection of human retinal pigment epithelial cells from oxidative damage using cysteine prodrugs
Bulumulla, Chandima,Catchpole, Timothy,Christie, Abigail,Csaky, Karl G.,Kularatne, Ruvanthi N.,Stefan, Mihaela C.,Takacs, Alison
, p. 386 - 394 (2020/04/17)
Age-related macular degeneration (AMD) is one of the major causes of vision loss in the elderly in most developed countries. Among other causes, oxidative stress in the retinal pigment epithelium (RPE) has been hypothesized to be a major driving force of AMD pathology. Oxidative stress could be treated by antioxidant administration into the RPE cells. However, to achieve high in-vivo efficacy of an antioxidant, it is imperative that the agent be able to penetrate the tissues and cells. Evidence suggests that lipophilicity governs cellular penetrance. Out of many antioxidant candidates, N-acetyl-L-cysteine (a prodrug of L-cysteine) (NAC) is a potent antioxidant as the bioavailability of the parent drug, L-cysteine, determines the production of glutathione; the universal antioxidant that regulates ROS. To increase the lipophilicity, four ester derivatives of N-acetylcysteine: N-acetylcysteine methyl ester, N-acetylcysteine ethyl ester, N-acetylcysteine propyl ester, and N-acetylcysteine butyl ester were synthesized. To mimic in vitro AMD conditions, hydroquinone, a component of cigarette smoke, was used as the oxidative insult. Cytosolic and mitochondrial protection against oxidative stress were tested using cytosolic and mitochondrial specific assays. The results provide evidence that these lipophilic cysteine prodrugs provide increased protection against oxidative stress in human RPE cells compared with NAC.