Back to Search Start Over

Acid Derivatives of Pyrazolo[1,5-a]pyrimidine as Aldose Reductase Differential Inhibitors.

Authors :
Balestri F
Quattrini L
Coviello V
Sartini S
Da Settimo F
Cappiello M
Moschini R
Del Corso A
Mura U
La Motta C
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.)

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