Terezia Teplanova
PC39 – Terezia Teplanova
Comenius University Bratislava, Faculty of Natural Sciences, Department of Organic Chemistry, Bratislava, Slovak Republic
teplanova16@uniba.sk
| Development of fluorinated triazinoindoles as highly potent and markedly selective aldose reductase inhibitors focused on prevention of diabetic complications |
| Terézia Teplanová1, Ambróz Almássy1, Andrej Boháč1, Lucia Kováčiková1,2 1 Comenius University Bratislava, Faculty of Natural Sciences, Department of Organic Chemistry, Ilkovičova 6, 841 04 Bratislava, Slovak Republic 2 Slovak Academy of Sciences, Institute of Experimental Pharmacology and Toxicology, CEM v.v.i., Dúbravská cesta 9, 841 04 Bratislava, Slovak Republic |
| Abstract A hyperglycemic state increases activation of the polyol pathway, which plays a key role in the pathogenesis of secondary diabetic complications. Inhibition of the first enzyme in the polyol pathway, aldose reductase, using therapeutics such as aldose reductase inhibitors (ARIs) has proven to be a promising target for the treatment of diabetic complications. In our previous projects, the ALR2 inhibitor cemtirestat (CMTI) was designed, which showed good inhibitory activity (IC50 = 116 nM), selectivity (SF = 302) and also antioxidant properties. [1] The latter developed bioisoster OTI was much more effective (IC50 = 42 nM) and selective (SF > 2 381) than CMTI. (Figure 1) [2] In order to further improve the inhibitor properties, we focused on the synthesis of a series of in silico designed fluorinated analogues of CMTI and its oxygen bioisostere otirestat (OTI) to increase activity, selectivity and drug-like properties. All these derivatives showed significant improvements in both activity and selectivity compared to unsubstituted analogues. The inhibitor (8-F)OTI proved to be most effective at nM concentration, IC50 = 15 nM, with a high selectivity towards ALR2 / ALR1 (SF > 6 667). Position 8 on the aromatic ring of the indole skeleton of the inhibitor was shown, by molecular modeling, to be the best within the framework of complementarity to the ALR2 enzyme. Simultaneously, introducing a substituent at this position minimizes stabilizing interactions in ALR1, thereby increasing selectivity. This work was supported by VEGA 2/0124/26, VEGA 2/0136/26, APVV-24-0388, APVV DS-FR-24-0052. |
| References [1] Štefek, M.; Šoltésová Prnová, M. Identification of Novel Aldose Reductase Inhibitors Based on Carboxymethylated Mercaptotriazinoindole Scaffold. J. Med. Chem. 2015, 58, 2649-2657. [2] Hlaváč, M.; Kováčiková, L. Development of Novel Oxotriazinoindole Inhibitors of Aldose Reductase: Isosteric Sulfur/Oxygen Replacement in the Thioxotriazinoindole Cemtirestat Markedly Improved Inhibition Selectivity. J. Med. Chem. 2020, 63, 369-381. |