CN128
(Synonyms: CN328) 目录号 : GC60719An orally bioavailable iron chelator
Cas No.:1335282-05-7
Sample solution is provided at 25 µL, 10mM.
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CN128 is an orally bioavailable iron chelator.1 It contains a side chain hydroxy group that acts as an alternate sacrificial glucuronidation site to alleviate metabolic inactivation at the 3-hydroxy group. CN128 increases iron mobilization by 24.8% in a 59Fe-ferritin-loaded rat model of iron overload when administered at doses of 150 and 450 ?mol/kg.
1.Chen, W., Yuan, X., Li, Z., et al.CN128: A new orally active hydroxypyridinone iron chelatorJ. Med. Chem.63(8)4215-4226(2020)
Cas No. | 1335282-05-7 | SDF | |
别名 | CN328 | ||
Canonical SMILES | CC1=C(O)C(O)=CC=[N+]1[C@H](CC2=CC=CC=C2)CO.[Cl-] | ||
分子式 | C15H18ClNO3 | 分子量 | 295.76 |
溶解度 | Methanol: 5mg/mL,Methanol:PBS (pH 7.2) (1:1): 0.5mg/mL | 储存条件 | Store at -20°C |
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1 mg | 5 mg | 10 mg | |
1 mM | 3.3811 mL | 16.9056 mL | 33.8112 mL |
5 mM | 0.6762 mL | 3.3811 mL | 6.7622 mL |
10 mM | 0.3381 mL | 1.6906 mL | 3.3811 mL |
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CN128: A New Orally Active Hydroxypyridinone Iron Chelator
J Med Chem 2020 Apr 23;63(8):4215-4226.PMID:32208614DOI:10.1021/acs.jmedchem.0c00137.
Deferoxamine, deferiprone, and deferasirox are used for the treatment of systemic iron overload, although they possess limitations due to lack of oral activity, lower efficacy, and side effects. These limitations led to a search for an orally active iron chelator with an improved therapeutic index. The lower efficacy of deferiprone is due to rapid glucuronidation, leading to the formation of a nonchelating metabolite. Here, we demonstrate that the influence of metabolism can be reduced by introducing a sacrificial site for glucuronidation. A log P-guided investigation of 20 hydroxpyridinones led to the identification of CN128. The Fe(III) affinity and metal selectivity of CN128 are similar to those of deferiprone, the log P value is more lipophilic, and its iron scavenging ability is superior. Overall, CN128 was demonstrated to be safe in a range of toxicity assessments and is now in clinical trials for the treatment of β-thalassemia after regular blood transfusion.
Effectiveness of the Iron Chelator CN128 in Mitigating the Formation of Dopamine Oxidation Products Associated with the Progression of Parkinson's Disease
ACS Chem Neurosci 2020 Nov 4;11(21):3646-3657.PMID:33143428DOI:10.1021/acschemneuro.0c00557.
The occurrence and progression of Parkinson's disease (PD) has been associated with the observation of elevated iron concentrations in the substantia nigra pars compacta (SNpc). While the reasons for the impact of elevated iron concentrations remain unclear, one hypothesis is that the presence of labile iron induces the oxidation of dopamine (DA) to toxic quinones such as aminochrome (DAC) and reactive oxygen species (ROS). As such, one of the proposed therapeutic strategies has been the use of iron chelators such as deferiprone (DFP) (which is recognized to have limitations related to its rapid degradation in the liver) to reduce the concentration of labile iron. In this study, a detailed investigation regarding the novel iron chelator, CN128, was conducted and a kinetic model developed to elucidate the fundamental behavior of this chelator. The results in this work reveal that CN128 is effective in alleviating the toxicity induced by iron and DA to neurons when DA is present at moderate concentrations. When all the iron is chelated by CN128, the formation of DAC and the oxidation of DA can be reduced to levels identical to that in the absence of iron. The production of H2O2 is lower than that generated via the autoxidation of the same amount of DA. However, when severe leakage of DA occurs, the application of CN128 is insufficient to alleviate the associated toxicity. This is attibuted to the less important role of iron in the production of toxic intermediates at high concentrations of DA. CN128 is superior to DFP with regard to the reduction in formation of DAC and elevation in DA concentration. In summary, the results of this study suggest that prodromal application of the chelator CN128 could be effective in preventing the onset and slowing the early stage development of PD symptoms associated with oxidants and toxic intermediates resulting from the iron-mediated oxidation of the neurotransmitter dopamine with CN128 likely to be superior to DFP in view of its greater in vivo availability and less problematic side effects.