Rational design and synthesis of novel N-benzylindole-based epalrestat analogs as selective aldose reductase inhibitors: An unexpected discovery of a new glucose-lowering agent (AK-4) acting as a mitochondrial uncoupler

Article

Author: Petrou, Anthi ; Santi, Alice ; Stefek, Milan ; Kovacikova, Lucia ; Kousaxidis, Antonios ; Paoli, Paolo ; Nicolaou, Ioannis ; Genovese, Massimo

Diabetes mellitus is one of the most frequent metabolic diseases associated with hyperglycemia. Although antidiabetic drugs reduce hyperglycemia, diabetic patients suffer from abnormal fluctuations in blood glucose levels leading to the onset of long-term complications. Aldose reductase inhibitors are considered a promising strategy for regulating the occurrence of diabetic-specific comorbidities. So far, epalrestat is the only drug being approved in Asian countries. In this paper, we ground our research in discovering novel epalrestat analogs that prevent chronic complications and normalize hyperglycemia. Herein, we describe the rational design and synthesis of four novel 4-thiazolidinone acetic acid derivatives (AK-1-4) being evaluated for their efficacy against aldose reductase from rat lenses and their specificity over the homologous enzyme from rat kidneys. AK-1-4 were also tested against human recombinant protein tyrosine phosphatase 1B as a key target in insulin sensitization and towards the closely related T-cell-derived enzyme. Docking analyses suggested possible binding modes on examined targets. The promising inhibitory profile of AK-4 sparked our interest in exploring its effect on the insulin-receptor signaling pathway and its ability to stimulate glucose uptake under ex vivo conditions. We further investigated the ability of AK-4 to target mitochondria acting as an uncoupling agent and impairing mitochondrial membrane potential. Herein, we report for the first time a new glucose-lowering agent (AK-4) that can combine alleviation for chronic diabetic complications without off-target adverse effects and antihyperglycemic efficacy through controlled mitochondrial uncoupling activity. Pharmacokinetic and toxicity studies in silico revealed optimal properties of AK-4 for oral administration without potential side effects.

01 Jan 2008·HemoglobinQ4 · MEDICINE

The Effects of Bicarbonate and its Combination with Chelating Agents Used for the Removal of Depleted Uranium in Rats

Q4 · MEDICINE

Article

Author: Mariko Nakamura ; Yuyuan Xie ; George J Kontoghiorghes ; Mizuyo Ikeda ; Akira Katoh ; Satoshi Fukuda ; Xueming Yan

The effects of bicarbonate and its combination with the chelating agents, deferiprone (L1), 4,6-dimethyl-1-hydroxypyrimidin-2(1H)-one (AK-4), catechol-3,6-bis(methyleneimino-diacetic-acid) (CBMIDA), and ethane-1-hydroxy-1,1-bisphoshonate (EHBP) in removing depleted uranium (DU) for radiation emergency medicine were examined. After the intramuscular injection of DU in rats, various time schedules of bicarbonate and chelating agent administration were tested. The results indicate that the bicarbonate helps increase significantly the effects of LI and AK-4, while there were no effects of using bicarbonate alone. The effects of bicarbonate on CBMIDA were unclear, and the effects of EHBP were negative. Further studies are necessary to obtain distinctly synergic effects by the combination of chelating agents with bicarbonate.

01 May 2005·Leukemia ResearchQ4 · MEDICINE

Cytokinetics and mechanism of action of AKO4: a novel nitrogen mustard targeted to bcr-abl

Q4 · MEDICINE

Article

Author: Bertrand J. Jean-Claude ; Athanasia Katsoulas ; Fouad Brahimi ; Zakaria Rachid ; James McNamee

The "combi-targeting" concept seeks to design molecules to not only block tyrosine kinase (TK) activity but also to induce DNA damage. Here we design AK04, a molecule that combines the pharmacophore chlorambucil with that of STI-571 (Gleevec). The results showed that although a less potent abl TK inhibitor than STI571, AK04 was capable of significantly blocking bcr-abl phosphorylation not only in a purified abl assay but also in the bcr-abl+ K562 cells. In contrast to STI571 and like chlorambucil, it induced a dose-dependent increase in DNA damage in these cells. More importantly, AK04 was 12-32-fold more potent than chlorambucil in all bcr-abl+ cells of our cell panel. In the isogenic human megakaryocytic Mo7e and Mo7/bcr-abl cells, AK04 selectively killed the bcr-abl transfectants. Flow cytometry revealed that despite being a five-fold less potent inhibitor of bcr-abl than STI-571, it induced a significant dose-dependent increase in levels of cell death by apoptosis in KU812 cells 24 h post-treatment. Under these conditions, chlorambucil did not induce any significant level of apoptosis. These results suggest that AK04 is a nitrogen mustard with binary bcr-abl/DNA targeting effects, a property that may account for its superior potency when compared with the classical mustard chlorambucil.

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Indication	Highest Phase	Country/Location	Organization	Date
Anaphylaxis	Preclinical	US	Allakos, Inc.	11 Nov 2022

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