Abstract
Fifteen compounds, sharing an indole-1-acetic acid moiety as a common fragment, were selected from commercial databases for testing aldose reductase inhibition. 3-Mercapto-5H-1,2,4-triazino[5,6-b]indole-5-acetic acid (13) was the most promising inhibitor, with an IC50 in the submicromolar range and high selectivity, relative to aldehyde reductase. The crystal structure of aldose reductase complexed with 13 revealed an interaction pattern explaining its high affinity. Physicochemical parameters underline the excellent "leadlikeness" of 13 as a promising candidate for further structure optimizations.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Acetic Acid / chemistry
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Acetic Acid / pharmacology
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Aldehyde Reductase / antagonists & inhibitors*
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Aldehyde Reductase / chemistry
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Aldehyde Reductase / metabolism
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Animals
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Crystallography, X-Ray
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Enzyme Inhibitors / chemistry*
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Enzyme Inhibitors / pharmacology*
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Humans
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Indoleacetic Acids / chemistry*
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Indoleacetic Acids / pharmacology*
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Lens, Crystalline / drug effects
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Lens, Crystalline / enzymology
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Lens, Crystalline / metabolism
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Male
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Models, Molecular
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Rats
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Rats, Wistar
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Sorbitol / metabolism
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Structure-Activity Relationship
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Sulfhydryl Compounds / chemistry*
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Sulfhydryl Compounds / pharmacology*
Substances
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Enzyme Inhibitors
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Indoleacetic Acids
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Sulfhydryl Compounds
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cemtirestat
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Sorbitol
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AKR1B1 protein, human
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Aldehyde Reductase
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Acetic Acid