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Decreasing acidity in a series of aldose reductase inhibitors: 2-Fluoro-4-(1H-pyrrol-1-yl)phenol as a scaffold for improved membrane permeationChatzopoulou, Maria ...Targeting long-term diabetic complications, as well as inflammatory pathologies, aldose reductase inhibitors (ARIs) have been gaining attention over the years. In the present work, in order to ... address the poor membrane permeation of previously reported ARIs, derivatives of N-phenylpyrrole, bearing groups with putative pKa Ž 7.4, were synthesized and evaluated for aldose reductase inhibitory activity. The 2-fluorophenol group proved the most promising moiety, and further modifications were explored. The most active compound (31), identified as a submicromolar inhibitor (IC50 = 0.443[micro] M), was also selective against the homologous enzyme aldehyde reductase. Cross-docking revealed that 31 displays a peculiar interaction network that may be responsible for high affinity. Physicochemical profiling of 31 showed a pKa of 7.64, rendering it less than 50% ionized in the physiological pH range, with potentially favorable membrane permeation. The latter was supported from the successful inhibition of sorbitol formation in rat lenses and the ability to permeate rat jejunum.Source: Bioorganic & Medicinal Chemistry. - ISSN 0968-0896 (Vol. 22, iss. 7, 2014, str. 2194-2207)Type of material - article, component partPublish date - 2014Language - englishCOBISS.SI-ID - 3622257
Author
Chatzopoulou, Maria |
Patsilinakos, Alexandros |
Vallianatou, Theodosia |
Soltesova Prnova, Marta |
Žakelj, Simon |
Ragno, Rino |
Stefek, Milan |
Kristl, Albin |
Tsantili-Kakoulidou, Anna |
Demopoulos, Vassilis J.
Topics
non-anionic aldose reductase inhibitors |
fluoroacetylation |
cross-docking |
physicochemical profiling |
inhibition of sorbitol accumulation
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Database name | Field | Year |
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Links to authors' personal bibliographies | Links to information on researchers in the SICRIS system |
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Chatzopoulou, Maria | |
Patsilinakos, Alexandros | |
Vallianatou, Theodosia | |
Soltesova Prnova, Marta | |
Žakelj, Simon | 22659 |
Ragno, Rino | |
Stefek, Milan | |
Kristl, Albin | 11122 |
Tsantili-Kakoulidou, Anna | |
Demopoulos, Vassilis J. |
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