title: Progresses in the pursuit of aldose reductase inhibitors: the structure-based lead optimization step.
abstract: Aldose reductase (ALR2) is a crucial enzyme in the development of the major complications of diabetes mellitus. Very recently it has been demonstrated that the ARL2 inhibitor, fidarestat, significantly prevents inflammatory signals (TNF-α, LPS) that cause cancer (colon, breast, prostate and lung), metastasis, asthma, and other inflammatory diseases. Currently, fidarestat is in phase III clinical trial for diabetic neuropathy and was found to be safe. Thus the finding of novel, potent ARL2 inhibitors is today more than in the past in great demand as they can pave the way for a novel therapeutic approach for a number of diseases besides the diabetes. Herein, starting from the virtual screening-derived ALR2 inhibitor S12728 (1), a rational receptor-based lead optimization has been undertaken. The design and synthetic efforts here reported led to the discovery of several new compounds endowed with low micromolar/submicromolar activities.
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Università di Salerno, Via Ponte Don Melillo 11c, 84084 Fisciano, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Ramunno
authors.forename: Sandro
authors.initials: S
authors.lastname: Cosconati
authors.forename: Stefania
authors.initials: S
authors.lastname: Sartini
authors.forename: Vita
authors.initials: V
authors.lastname: Maglio
authors.forename: Sara
authors.initials: S
authors.lastname: Angiuoli
authors.forename: Valeria
authors.initials: V
authors.lastname: La Pietra
authors.forename: Salvatore
authors.initials: S
authors.lastname: Di Maro
authors.forename: Mariateresa
authors.initials: M
authors.lastname: Giustiniano
authors.forename: Concettina
authors.initials: C
authors.lastname: La Motta
authors.forename: Federico
authors.initials: F
authors.lastname: Da Settimo
authors.forename: Luciana
authors.initials: L
authors.lastname: Marinelli
authors.forename: Ettore
authors.initials: E
authors.lastname: Novellino
mesh_terms: D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D020134:Catalytic Domain; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D013329:Structure-Activity Relationship; D014584:User-Computer Interface
chemical_list: D004791:Enzyme Inhibitors; D000449:Aldehyde Reductase