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[5-(Benzyloxy)-1H-indol-1-yl]acetic acid, an aldose reductase inhibitor and PPARγ ligand.
- Source :
-
Acta biochimica Polonica [Acta Biochim Pol] 2015; Vol. 62 (3), pp. 523-8. Date of Electronic Publication: 2015 Sep 08. - Publication Year :
- 2015
-
Abstract
- Based on overlapping structural requirements for both efficient aldose reductase inhibitors and PPAR ligands, [5-(benzyloxy)-1H-indol-1-yl]acetic acid (compound 1) was assessed for inhibition of aldose reductase and ability to interfere with PPARγ. Aldose reductase inhibition by 1 was characterized by IC50 in submicromolar and low micromolar range, for rat and human enzyme, respectively. Selectivity in relation to the closely related rat kidney aldehyde reductase was characterized by approx. factor 50. At organ level in isolated rat lenses, compound 1 significantly inhibited accumulation of sorbitol in a concentration-dependent manner. To identify crucial interactions within the enzyme binding site, molecular docking simulations were performed. Based on luciferase reporter assays, compound 1 was found to act as a ligand for PPARγ, yet with rather low activity. On balance, compound 1 is suggested as a promising lead-like scaffold for agents with the potential to interfere with multiple targets in diabetes.
- Subjects :
- Aldehyde Reductase metabolism
Animals
Binding Sites
Diabetes Mellitus metabolism
Enzyme Inhibitors pharmacology
Humans
Indoles metabolism
Inhibitory Concentration 50
Kidney enzymology
Lens, Crystalline enzymology
Ligands
Luciferases metabolism
Male
Molecular Conformation
Protein Binding
Rats
Rats, Wistar
Thiazoles chemistry
Acetic Acid chemistry
Aldehyde Reductase antagonists & inhibitors
Indoleacetic Acids chemistry
PPAR gamma metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1734-154X
- Volume :
- 62
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Acta biochimica Polonica
- Publication Type :
- Academic Journal
- Accession number :
- 26345091
- Full Text :
- https://doi.org/10.18388/abp.2014_953