title: Enhancing activity and selectivity in a series of pyrrol-1-yl-1-hydroxypyrazole-based aldose reductase inhibitors: The case of trifluoroacetylation.
abstract: Aldose reductase (ALR2) has been the target of therapeutic intervention for over 40 years; first, for its role in long-term diabetic complications and more recently as a key mediator in inflammation and cancer. However, efforts to prepare small-molecule aldose reductase inhibitors (ARIs) have mostly yielded carboxylic acids with rather poor pharmacokinetics. To address this limitation, the 1-hydroxypyrazole moiety has been previously established as a bioisostere of acetic acid in a group of aroyl-substituted pyrrolyl derivatives. In the present work, optimization of this new class of ARIs was achieved by the addition of a trifluoroacetyl group on the pyrrole ring. Eight novel compounds were synthesized and tested for their inhibitory activity towards ALR2 and selectivity against aldehyde reductase (ALR1). All compounds proved potent and selective inhibitors of ALR2 (IC50/ALR2= 0.043-0.242 μΜ, Selectivity index = 190-858), whilst retaining a favorable physicochemical profile. The most active (4g) and selective (4d) compounds were further evaluated for their ability to inhibit sorbitol formation in rat lenses ex vivo and to exhibit substrate-specific inhibition.
authors.affiliation: Department of Pharmaceutical Chemistry, School of Pharmacy, Faculty of Health Sciences, Aristotle University of Thessaloniki, 54214 Thessaloniki, Greece.
authors.forename: Nikolaos
authors.initials: N
authors.lastname: Papastavrou
authors.affiliation: Department of Pharmaceutical Chemistry, School of Pharmacy, Faculty of Health Sciences, Aristotle University of Thessaloniki, 54214 Thessaloniki, Greece. Electronic address: maria.chatzopoulou@chem.ox.ac.uk.
authors.forename: Maria
authors.initials: M
authors.lastname: Chatzopoulou
authors.affiliation: Institute of Experimental Pharmacology and Toxicology, Slovak Academy of Sciences, Dubravska Cesta 9, 841 04 Bratislava, Slovakia.
authors.forename: Jana
authors.initials: J
authors.lastname: Ballekova
authors.affiliation: Department of Biology, Biochemistry Unit, University of Pisa, via S. Zeno, 51, Pisa, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Cappiello
authors.affiliation: Department of Biology, Biochemistry Unit, University of Pisa, via S. Zeno, 51, Pisa, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Moschini
authors.affiliation: Department of Biology, Biochemistry Unit, University of Pisa, via S. Zeno, 51, Pisa, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Balestri
authors.affiliation: Rome Center for Molecular Design, Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza, Università di Roma, P.le A.Moro 5, 00185 Rome, Italy; Alchemical Dynamics Srl, 00125 Rome, Italy.
authors.forename: Alexandros
authors.initials: A
authors.lastname: Patsilinakos
authors.affiliation: Rome Center for Molecular Design, Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza, Università di Roma, P.le A.Moro 5, 00185 Rome, Italy; Alchemical Dynamics Srl, 00125 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: Department of Pharmaceutical Chemistry, School of Pharmacy, Faculty of Health Sciences, Aristotle University of Thessaloniki, 54214 Thessaloniki, Greece. Electronic address: inikolao@pharm.auth.gr.
authors.forename: Ioannis
authors.initials: I
authors.lastname: Nicolaou
mesh_terms: D000107:Acetylation; D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors*; D000818:Animals; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D007908:Lens, Crystalline / Q000378:metabolism; D011720:Pyrazoles / Q000737:chemistry / Q000494:pharmacology*; D011758:Pyrroles / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D012680:Sensitivity and Specificity; D013012:Sorbitol / Q000037:antagonists & inhibitors; D014269:Trifluoroacetic Acid / Q000737:chemistry
chemical_list: D004791:Enzyme Inhibitors; D011720:Pyrazoles; D011758:Pyrroles; D013012:Sorbitol; D014269:Trifluoroacetic Acid; D000449:Aldehyde Reductase
keywords: 1-Hydroxypyrazole; Aldose reductase inhibitors; Differential inhibitors; Sorbitol accumulation; Trifluoroacetylation