Design and synthesis of 2-(arylamino)-4(3H)-quinazolinones as novel inhibitors of rat lens aldose reductase

• Published in: Journal of medicinal chemistry 1986-05, Vol.29 (5), p.627-629
• Main Authors: DeRuiter, Jack, Brubaker, Abram N, Millen, Jane, Riley, Thomas N
• Format: Article
• Language: English
• Subjects: Aldehyde Reductase - antagonists & inhibitors; Animals; Chemistry; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - pharmacology; Exact sciences and technology; Heterocyclic compounds; Heterocyclic compounds with several n hetero atoms in the same ring, in separated rings or in fused rings; Lens, Crystalline - enzymology; Organic chemistry; Preparations and properties; Quinazolines - chemical synthesis; Quinazolines - pharmacology; Rats; Sugar Alcohol Dehydrogenases - antagonists & inhibitors
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00155a007

A number of 2-(arylamino)-4(3H)-quinazolinones (2a-i) that possess several of the pharmacophore moieties necessary for binding to the inhibitor site of the enzyme aldose reductase were synthesized and tested for their ability to inhibit crude aldose reductase obtained from rat lens. Only those quinazolinones that possess an acidic moiety on the 2-(arylamino) substituent were found to display significant inhibitory activity. Of these, the most potent compound is the 4'-CO2H derivative (2i) with an IC50 of 34 microM, while the least potent is the 4'-OH derivative (2c) with an IC50 of 75 microM. All of the 2-(arylamino)-4(3H)-quinazolinones tested are less potent than other known inhibitors of aldose reductase, such as alrestatin and sorbinil, indicating that the pharmacophore moieties present in these compounds may not be positioned optimally relative to one another for maximal interaction with the enzyme.