Enhancing activity and selectivity in a series of pyrrol-1-yl-1-hydroxypyrazole-based aldose reductase inhibitors: The case of trifluoroacetylation

• Published in: European journal of medicinal chemistry 2017-04, Vol.130, p.328-335
• Main Authors: Papastavrou, Nikolaos, Chatzopoulou, Maria, Ballekova, Jana, Cappiello, Mario, Moschini, Roberta, Balestri, Francesco, Patsilinakos, Alexandros, Ragno, Rino, Stefek, Milan, Nicolaou, Ioannis
• Format: Article
• Language: English
• Subjects: 1-Hydroxypyrazole; Acetylation; Aldehyde Reductase - antagonists & inhibitors; Aldose reductase inhibitors; Animals; Differential inhibitors; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Lens, Crystalline - metabolism; Pyrazoles - chemistry; Pyrazoles - pharmacology; Pyrroles - chemistry; Pyrroles - pharmacology; Rats; Sensitivity and Specificity; Sorbitol - antagonists & inhibitors; Sorbitol accumulation; Trifluoroacetic Acid - chemistry; Trifluoroacetylation
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2017.02.053

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. [Display omitted] •Eight novel trifluoroacetylated pyrrole derivatives were synthesized.•All compounds were potent and selective in vitro inhibitors of ALR2.•Compounds 4d and 4g inhibited sorbitol formation in rat lenses ex vivo.•Kinetics and differential inhibition of 4d and 4g were also studied.•4g (IC50 = 0.043 μΜ) is a potent and selective ARI with a good physicochemical profile.