title: Novel, highly potent aldose reductase inhibitors: cyano(2-oxo-2,3-dihydroindol-3-yl)acetic acid derivatives.
abstract: Cyano(2-oxo-2,3-dihydroindol-3-yl)acetic acid derivatives were synthesized and tested as a novel class of aldose reductase (ALR2) inhibitors. Each compound was evaluated as a diastereomeric mixture, due to tautomeric equilibria in solution. The parent compound 39 exhibited a good inhibitory activity with an IC(50) value of 0.85 microM, similar to that of the well-known ARI sorbinil (IC(50) 0.50 microM). The concurrent introduction of a halogen and a lipophilic group in the 5- and in the 1-positions, respectively, of the indole nucleus of 39, gave compound 55, cyano[5-fluoro-1-(4-methylbenzyl)-2-oxo-2,3-dihydroindol-3-yl]acetic acid, which displayed the highest activity (IC(50) 0.075 microM, very close to that of tolrestat IC(50) 0.046 microM), with a good selectivity toward ALR2 compared with aldehyde reductase (ALR1) (16.4-fold), and no appreciable inhibitory properties against sorbitol dehydrogenase (SD), or glutathione reductase (GR). The isopropyl ester 59, a prodrug of 55, was found to be almost as effective as tolrestat in preventing cataract development in severely galactosemic rats when administered as an eye drop solution. Docking simulation of 55 into a three-dimensional model of human ALR2 made it possible to formulate the hypothesis that the 2-hydroxy tautomer was the active species binding into the catalytic site of the enzyme. This was fully consistent with the structure-activity relationships within this series of cyanooxoindolylacetic acid derivatives.
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Università di Pisa, Via Bonanno 6, Italy. fsettimo@farm.unipi.it
authors.forename: Federico
authors.initials: F
authors.lastname: Da Settimo
authors.forename: Giampaolo
authors.initials: G
authors.lastname: Primofiore
authors.forename: Antonio
authors.initials: A
authors.lastname: Da Settimo
authors.forename: Concettina
authors.initials: C
authors.lastname: La Motta
authors.forename: Francesca
authors.initials: F
authors.lastname: Simorini
authors.forename: Ettore
authors.initials: E
authors.lastname: Novellino
authors.forename: Giovanni
authors.initials: G
authors.lastname: Greco
authors.forename: Antonio
authors.initials: A
authors.lastname: Lavecchia
authors.forename: Enrico
authors.initials: E
authors.lastname: Boldrini
mesh_terms: D000085:Acetates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors*; D000818:Animals; D002386:Cataract / Q000209:etiology / Q000517:prevention & control; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D005693:Galactosemias / Q000150:complications; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008958:Models, Molecular; D009883:Ophthalmic Solutions; D051381:Rats; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000085:Acetates; D004791:Enzyme Inhibitors; D007211:Indoles; D009883:Ophthalmic Solutions; C473674:cyano(5-fluoro-1-(4-methylbenzyl)-2-oxo-2,3-dihydroindol-3-yl)acetic acid; D000449:Aldehyde Reductase