1-Hydroxypyrazole as a bioisostere of the acetic acid moiety in a series of aldose reductase inhibitors

Therapeutic intervention with aldose reductase inhibitors appears to be promising for major pathological conditions (i.e., long-term diabetic complications and inflammatory pathologies). So far, however, clinical candidates have failed due to adverse side-effects (spiroimides) or poor bioavailabilit...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry 2013-09, Vol.21 (17), p.4951-4957
Main Authors: Papastavrou, Nikolaos, Chatzopoulou, Maria, Pegklidou, Kyriaki, Nicolaou, Ioannis
Format: Article
Language:English
Subjects:
acetic acid
Acetic Acid - chemistry
adverse effects
aldehyde reductase
Aldehyde Reductase - antagonists & inhibitors
Aldehyde Reductase - metabolism
Aldose reductase inhibitors
Animals
bioavailability
Bioisosterism
chemistry
diabetic complications
Enzyme Inhibitors - chemical synthesis
Enzyme Inhibitors - chemistry
Enzyme Inhibitors - metabolism
Inflammatory pathologies
Kidney - enzymology
Kinetics
Lens Cortex, Crystalline - enzymology
Long-term diabetic complications
Molecular obesity
Protein Binding
Pyrazoles - chemical synthesis
Pyrazoles - chemistry
Pyrazoles - metabolism
Rats
Structure-Activity Relationship
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Summary:Therapeutic intervention with aldose reductase inhibitors appears to be promising for major pathological conditions (i.e., long-term diabetic complications and inflammatory pathologies). So far, however, clinical candidates have failed due to adverse side-effects (spiroimides) or poor bioavailability (carboxylic acids). In this work, we succeeded in the bioisosteric replacement of an acetic acid moiety with that of 1-hydroxypyrazole. This new scaffold appears to have a superior physicochemical profile, while attaining inhibitory activity in the submicromolar range.
ISSN:0968-0896
1464-3391
DOI:10.1016/j.bmc.2013.06.062