Substituted pyrrol-1-ylacetic acids that combine aldose reductase enzyme inhibitory activity and ability to prevent the nonenzymatic irreversible modification of proteins from monosaccharides.

Article Details

Citation

Nicolaou I, Demopoulos VJ

Substituted pyrrol-1-ylacetic acids that combine aldose reductase enzyme inhibitory activity and ability to prevent the nonenzymatic irreversible modification of proteins from monosaccharides.

J Med Chem. 2003 Jan 30;46(3):417-26.

PubMed ID
12540241 [ View in PubMed
]
Abstract

Starting from the known inhibitory activity of (3-benzoylpyrrol-1-yl)acetic acid (I) and (2-benzoylpyrrol-1-yl)acetic acid (II), a series of 3-aroyl and 2,4-bis-aroyl derivatives (54-75) were synthesized and tested for inhibition of aldose reductase, an enzyme involved in the appearance of diabetic complications. It was found that a number of the tested compounds exhibited considerable activity in the micromolar range. Important structural features for the potent compounds is the presence of substituents with relatively low Hammett sigma values and/or moieties which increase their overall aromatic area. The most active derivative was the [2,4-bis(4-methoxybenzoyl)pyrrol-1-yl]acetic acid (75), with potency favorably compared to known ARIs such as tolrestat, epalrestat, zopolrestat, and fidarestat. Four selected derivatives were also evaluated for their ability to interfere with the oxidative modification of serum albumin in an in vitro experimental glycation model of diabetes mellitus. All of them showed considerable activity, comparable to the known inhibitor trolox. Our results, taken together, indicate that compound 75 combines favorably two biological activities directly connected to a number of pathological conditions related to the chronic diabetes mellitus.

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
(S,R)-fidarestatAldose reductaseIC 50 (nM)35N/AN/ADetails
TolrestatAldose reductaseIC 50 (nM)35N/AN/ADetails
ZopolrestatAldose reductaseIC 50 (nM)3.1N/AN/ADetails