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Acid Derivatives of Pyrazolo[1,5-a]pyrimidine as Aldose Reductase Differential Inhibitors.
- Source :
-
Cell chemical biology [Cell Chem Biol] 2018 Nov 15; Vol. 25 (11), pp. 1414-1418.e3. Date of Electronic Publication: 2018 Aug 16. - Publication Year :
- 2018
-
Abstract
- Aldose reductase (AKR1B1), the key enzyme of the polyol pathway, plays a crucial role in the development of long-term complications affecting diabetic patients. Nevertheless, the expedience of inhibiting this enzyme to treat diabetic complications has failed, due to the emergence of side effects from compounds under development. Actually AKR1B1 is a Janus-faced enzyme which, besides ruling the polyol pathway, takes part in the antioxidant defense mechanism of the body. In this work we report the evidence that a class of compounds, characterized by a pyrazolo[1,5-a]pyrimidine core and an ionizable fragment, modulates differently the catalytic activity of the enzyme, depending on the presence of specific substrates such as sugar, toxic aldehydes, and glutathione conjugates of toxic aldehydes. The study stands out as a systematic attempt to generate aldose reductase differential inhibitors (ARDIs) intended to target long-term diabetic complications while leaving unaltered the detoxifying role of the enzyme.<br /> (Copyright © 2018 Elsevier Ltd. All rights reserved.)
- Subjects :
- Aldehyde Reductase metabolism
Diabetes Complications drug therapy
Diabetes Complications metabolism
Diabetes Mellitus drug therapy
Diabetes Mellitus metabolism
Drug Discovery
Humans
Substrate Specificity
Aldehyde Reductase antagonists & inhibitors
Enzyme Inhibitors chemistry
Enzyme Inhibitors pharmacology
Pyrazoles chemistry
Pyrazoles pharmacology
Pyridines chemistry
Pyridines pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 2451-9448
- Volume :
- 25
- Issue :
- 11
- Database :
- MEDLINE
- Journal :
- Cell chemical biology
- Publication Type :
- Academic Journal
- Accession number :
- 30122369
- Full Text :
- https://doi.org/10.1016/j.chembiol.2018.07.008