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Progresses in the pursuit of aldose reductase inhibitors: the structure-based lead optimization step.
- Source :
-
European journal of medicinal chemistry [Eur J Med Chem] 2012 May; Vol. 51, pp. 216-26. Date of Electronic Publication: 2012 Mar 05. - Publication Year :
- 2012
-
Abstract
- Aldose reductase (ALR2) is a crucial enzyme in the development of the major complications of diabetes mellitus. Very recently it has been demonstrated that the ARL2 inhibitor, fidarestat, significantly prevents inflammatory signals (TNF-α, LPS) that cause cancer (colon, breast, prostate and lung), metastasis, asthma, and other inflammatory diseases. Currently, fidarestat is in phase III clinical trial for diabetic neuropathy and was found to be safe. Thus the finding of novel, potent ARL2 inhibitors is today more than in the past in great demand as they can pave the way for a novel therapeutic approach for a number of diseases besides the diabetes. Herein, starting from the virtual screening-derived ALR2 inhibitor S12728 (1), a rational receptor-based lead optimization has been undertaken. The design and synthetic efforts here reported led to the discovery of several new compounds endowed with low micromolar/submicromolar activities.<br /> (Copyright © 2012 Elsevier Masson SAS. All rights reserved.)
- Subjects :
- Aldehyde Reductase chemistry
Catalytic Domain
Enzyme Inhibitors chemistry
Enzyme Inhibitors pharmacokinetics
Inhibitory Concentration 50
Models, Molecular
Structure-Activity Relationship
User-Computer Interface
Aldehyde Reductase antagonists & inhibitors
Drug Evaluation, Preclinical methods
Enzyme Inhibitors pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1768-3254
- Volume :
- 51
- Database :
- MEDLINE
- Journal :
- European journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 22436396
- Full Text :
- https://doi.org/10.1016/j.ejmech.2012.02.045