title: Decreasing acidity in a series of aldose reductase inhibitors: 2-Fluoro-4-(1H-pyrrol-1-yl)phenol as a scaffold for improved membrane permeation.
abstract: Targeting long-term diabetic complications, as well as inflammatory pathologies, aldose reductase inhibitors (ARIs) have been gaining attention over the years. In the present work, in order to address the poor membrane permeation of previously reported ARIs, derivatives of N-phenylpyrrole, bearing groups with putative pKa≥7.4, were synthesized and evaluated for aldose reductase inhibitory activity. The 2-fluorophenol group proved the most promising moiety, and further modifications were explored. The most active compound (31), identified as a submicromolar inhibitor (IC50=0.443μM), was also selective against the homologous enzyme aldehyde reductase. Cross-docking revealed that 31 displays a peculiar interaction network that may be responsible for high affinity. Physicochemical profiling of 31 showed a pKa of 7.64, rendering it less than 50% ionized in the physiological pH range, with potentially favorable membrane permeation. The latter was supported from the successful inhibition of sorbitol formation in rat lenses and the ability to permeate rat jejunum.
authors.affiliation: Department of Pharmaceutical Chemistry, School of Pharmacy, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece.
authors.forename: Maria
authors.initials: M
authors.lastname: Chatzopoulou
authors.affiliation: Rome Center for Molecular Design, Dipartimento di Chimica e Tecnologie del Farmaco, University of Rome 'Sapienza', 00185 Rome, Italy.
authors.forename: Alexandros
authors.initials: A
authors.lastname: Patsilinakos
authors.affiliation: Department of Pharmaceutical Chemistry, School of Pharmacy, University of Athens, Panepistimiopolis, Zografou, 157 71 Athens, Greece.
authors.forename: Theodosia
authors.initials: T
authors.lastname: Vallianatou
authors.affiliation: Institute of Experimental Pharmacology and Toxicology, Slovak Academy of Sciences, Dubravska cesta 9, 841 04 Bratislava, Slovakia.
authors.forename: Marta Soltesova
authors.initials: MS
authors.lastname: Prnova
authors.affiliation: Faculty of Pharmacy, University of Ljubljana, 1000 Ljubljana, Slovenia.
authors.forename: Simon
authors.initials: S
authors.lastname: Zakelj
authors.affiliation: Rome Center for Molecular Design, Dipartimento di Chimica e Tecnologie del Farmaco, University of Rome 'Sapienza', 00185 Rome, Italy.
authors.forename: Rino
authors.initials: R
authors.lastname: Ragno
authors.affiliation: Institute of Experimental Pharmacology and Toxicology, Slovak Academy of Sciences, Dubravska cesta 9, 841 04 Bratislava, Slovakia.
authors.forename: Milan
authors.initials: M
authors.lastname: Stefek
authors.affiliation: Faculty of Pharmacy, University of Ljubljana, 1000 Ljubljana, Slovenia.
authors.forename: Albin
authors.initials: A
authors.lastname: Kristl
authors.affiliation: Department of Pharmaceutical Chemistry, School of Pharmacy, University of Athens, Panepistimiopolis, Zografou, 157 71 Athens, Greece.
authors.forename: Anna
authors.initials: A
authors.lastname: Tsantili-Kakoulidou
authors.affiliation: Department of Pharmaceutical Chemistry, School of Pharmacy, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece. Electronic address: vdem@pharm.auth.gr.
authors.forename: Vassilis J
authors.initials: VJ
authors.lastname: Demopoulos
mesh_terms: D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D002463:Cell Membrane Permeability / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D007583:Jejunum / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D007909:Lenses; D008297:Male; D008958:Models, Molecular; D015394:Molecular Structure; D010636:Phenols / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011758:Pyrroles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013012:Sorbitol / Q000037:antagonists & inhibitors / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: C000593124:1-(4-benzoyl-1-(3-fluoro-4-hydroxyphenyl)-1H-pyrrol-2-yl)-2,2-difluoroethanone; D004791:Enzyme Inhibitors; D010636:Phenols; D011758:Pyrroles; D013012:Sorbitol; D000449:Aldehyde Reductase
keywords: Cross-docking; Fluoroacetylation; Inhibition of sorbitol accumulation; Non-anionic aldose reductase inhibitors; Physicochemical profiling