title: [1,2,4]Triazino[4,3-a]benzimidazole acetic acid derivatives: a new class of selective aldose reductase inhibitors.
abstract: Acetic acid derivatives of [1,2,4]triazino[4,3-a]benzimidazole (TBI) were synthesized and tested in vitro and in vivo as a novel class of aldose reductase (ALR2) inhibitors. Compound 3, (10-benzyl[1,2,4]triazino[4,3-a]benzimidazol-3,4(10H)-dion-2-yl)acetic acid, displayed the highest inhibitory activity (IC(50) = 0.36 microM) and was found to be effective in preventing cataract development in severely galactosemic rats when administered as an eyedrop solution. All the compounds investigated were selective for ALR2, since none of them inhibited appreciably aldehyde reductase, sorbitol dehydrogenase, or glutathione reductase. The activity of 3 was lowered by inserting various substituents on the pendant phenyl ring, by shifting the acetic acid moiety from the 2 to the 3 position of the TBI nucleus, or by cleaving the TBI system to yield benzimidazolylidenehydrazines as open-chain analogues. A three-dimensional model of human ALR2 was built, taking into account the conformational changes induced by the binding of inhibitors such as zopolrestat, to simulate the docking of 3 into the enzyme active site. The theoretical binding mode of 3 was fully consistent with the structure-activity relationships in the TBI series and will guide the design of novel ALR2 inhibitors.
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Università di Pisa, Via Bonanno 6, 56126 Pisa, Italy. fsettimo@farm.unipi.it
authors.forename: F
authors.initials: F
authors.lastname: Da Settimo
authors.forename: G
authors.initials: G
authors.lastname: Primofiore
authors.forename: A
authors.initials: A
authors.lastname: Da Settimo
authors.forename: C
authors.initials: C
authors.lastname: La Motta
authors.forename: S
authors.initials: S
authors.lastname: Taliani
authors.forename: F
authors.initials: F
authors.lastname: Simorini
authors.forename: E
authors.initials: E
authors.lastname: Novellino
authors.forename: G
authors.initials: G
authors.lastname: Greco
authors.forename: A
authors.initials: A
authors.lastname: Lavecchia
authors.forename: E
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; D001562:Benzimidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D002386:Cataract / Q000209:etiology / Q000517:prevention & control; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D005693:Galactosemias / Q000150:complications; D006801:Humans; D008958:Models, Molecular; D009883:Ophthalmic Solutions; D011485:Protein Binding; D051381:Rats; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014227:Triazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: C442801:(10-benzyl-(1,2,4)triazino(4,3-a)benzimidazol-3,4(10H)-dion-2-yl)acetic acid; D000085:Acetates; D001562:Benzimidazoles; D004791:Enzyme Inhibitors; D009883:Ophthalmic Solutions; D014227:Triazines; D000449:Aldehyde Reductase