title: N-(Aroyl)-N-(arylmethyloxy)-α-alanines: Selective inhibitors of aldose reductase.
abstract: Aldose reductase (ALR2), a NADPH-dependent reductase, is the first and rate-limiting enzyme of the polyol pathway of glucose metabolism and is implicated in the pathogenesis of secondary diabetic complications. In the last decades, this enzyme has been targeted for inhibition but despite the numerous efforts made to identify potent and safe ALR2 inhibitors, many clinical candidates have been a failure. For this reason the research of new ALR2 inhibitors highly effective, selective and with suitable pharmacokinetic properties is still of great interest. In this paper some new N-(aroyl)-N-(arylmethyloxy)alanines have been synthesized and tested for their ability to inhibit ALR2. Some of the synthesized compounds exhibit IC50in the low micromolar range and all have proved to be highly selective towards ALR2. The N-(aroyl)-N-(arylmethyloxy)-α-alanines are a promising starting point for the development of new ALR2 selective drugs with the aim of delaying the onset of diabetic complications.
authors.affiliation: Dipartimento di Farmacia, Università di Pisa, Via Bonanno 6, 56126 Pisa, Italy. Electronic address: susanna.nencetti@farm.unipi.it.
authors.forename: Susanna
authors.initials: S
authors.lastname: Nencetti
authors.affiliation: Dipartimento di Farmacia, Università di Pisa, Via Bonanno 6, 56126 Pisa, Italy.
authors.forename: Concettina
authors.initials: C
authors.lastname: La Motta
authors.affiliation: Dipartimento di Farmacia, Università di Pisa, Via Bonanno 6, 56126 Pisa, Italy.
authors.forename: Armando
authors.initials: A
authors.lastname: Rossello
authors.affiliation: Dipartimento di Farmacia, Università di Pisa, Via Bonanno 6, 56126 Pisa, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Sartini
authors.affiliation: Dipartimento di Farmacia, Università di Pisa, Via Bonanno 6, 56126 Pisa, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Nuti
authors.affiliation: CEA, iBiTec-S, Service d'Ingénierie Moléculaire des Protéines (SIMOPRO), Gif-sur-Yvette F-91191, France.
authors.forename: Lidia
authors.initials: L
authors.lastname: Ciccone
authors.affiliation: Dipartimento di Farmacia, Università di Pisa, Via Bonanno 6, 56126 Pisa, Italy; Dipartimento di Scienze della Terra, Università di Pisa, Via S. Maria 53, 56126 Pisa, Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Orlandini
mesh_terms: D000409:Alanine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D048909:Diabetes Complications / Q000201:enzymology / Q000517:prevention & control; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D007004:Hypoglycemic Agents / Q000737:chemistry / Q000494:pharmacology; D051381:Rats
chemical_list: D004791:Enzyme Inhibitors; D007004:Hypoglycemic Agents; C576693:Akr1b1 protein, rat; D000449:Aldehyde Reductase; D000409:Alanine
keywords: Aldose reductase (ALR2); Aldose reductase selective inhibitors; Diabetes mellitus; α-Alanines