[5-(Benzyloxy)-1H-indol-1-yl]acetic acid, an aldose reductase inhibitor and PPARγ ligand.
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.
Institute of Experimental Pharmacology and Toxicology, Slovak Academy of Sciences, Bratislava, Slovakia.
Marta
M
Soltesova Prnova
Institute of Experimental Pharmacology and Toxicology, Slovak Academy of Sciences, Bratislava, Slovakia.
Magdalena
M
Majekova
Institute of Experimental Pharmacology and Toxicology, Slovak Academy of Sciences, Bratislava, Slovakia.
Ivana
I
Milackova
Department of Chemical and Physical Biology, Centro de Investigaciones Biológicas, CSIC, Madrid, Spain.
Beatriz
B
Díez-Dacal
Department of Chemical and Physical Biology, Centro de Investigaciones Biológicas, CSIC, Madrid, Spain.
Dolores
D
Pérez-Sala
Department of Biological Sciences, Middle East Technical University, Ankara, Turkey.
Muserref Seyma
MS
Ceyhan
Department of Biological Sciences, Middle East Technical University, Ankara, Turkey.
Sreeparna
S
Banerjee
Institute of Experimental Pharmacology and Toxicology, Slovak Academy of Sciences, Bratislava, Slovakia.
Milan
M
Stefek
D019342:Acetic Acid / Q000737:chemistry*; D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D001665:Binding Sites; D003920:Diabetes Mellitus / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007210:Indoleacetic Acids / Q000737:chemistry*; D007211:Indoles / Q000378:metabolism; D020128:Inhibitory Concentration 50; D007668:Kidney / Q000201:enzymology; D007908:Lens, Crystalline / Q000201:enzymology; D008024:Ligands; D008156:Luciferases / Q000378:metabolism; D008297:Male; D008968:Molecular Conformation; D047495:PPAR gamma / Q000378:metabolism*; D011485:Protein Binding; D051381:Rats; D017208:Rats, Wistar; D013844:Thiazoles / Q000737:chemistry
C000609325:(5-(benzyloxy)-1H-indol-1-yl)acetic acid; D004791:Enzyme Inhibitors; D007210:Indoleacetic Acids; D007211:Indoles; D008024:Ligands; D047495:PPAR gamma; D013844:Thiazoles; C500848:lidorestat; D000449:Aldehyde Reductase; D008156:Luciferases; D019342:Acetic Acid