Design, synthesis, in vitro, in vivo and in silico pharmacological characterization of antidiabetic N-Boc-l-tyrosine-based compounds

• Published in: Biomedicine & pharmacotherapy 2018-12, Vol.108, p.670-678
• Main Authors: Herrera-Rueda, Miguel Ángel, Tlahuext, Hugo, Paoli, Paolo, Giacoman-Martínez, Abraham, Almanza-Pérez, Julio César, Pérez-Sánchez, Horacio, Gutiérrez-Hernández, Abraham, Chávez-Silva, Fabiola, Dominguez-Mendoza, Elix Alberto, Estrada-Soto, Samuel, Navarrete-Vazquez, Gabriel
• Format: Article
• Language: English
• Subjects: 3T3 Cells; Adipocytes - drug effects; Adipocytes - metabolism; Animals; Blood Glucose - drug effects; Cell Line; Computer Simulation; Diabetes; Disease Models, Animal; Drug design; Fatty Acid Transport Proteins - metabolism; Glucose Tolerance Test - methods; Glucose Transporter Type 4 - metabolism; GLUT-4; Hyperglycemia - drug therapy; Hyperglycemia - metabolism; Hypoglycemic Agents - pharmacology; Mice; Molecular Docking Simulation; Polypharmacology; PPAR; PPAR gamma - metabolism; PTP-1B; RNA, Messenger - metabolism; Tyrosine - pharmacology
• ISSN: 0753-3322; 1950-6007
• DOI: 10.1016/j.biopha.2018.09.074

[Display omitted] •Five N-Boc-l-tyrosine derivatives were designed as antidiabetic compounds.•Compounds 1 and 3 showed polypharmacological activities in the in vitro assays.•Both compounds were orally actives in the in vivo diabetes mellitus mice model.•1 and 3 could be considered as promising multitarget antidiabetic drug candidates. In this study, we synthesized five N-Boc-L-tyrosine-based analogues to glitazars. The in vitro effects of compounds 1–5 on protein tyrosine phosphatase 1B (PTP-1B), peroxisome proliferator-activated receptor alpha and gamma (PPARα/γ), glucose transporter type-4 (GLUT-4) and fatty acid transport protein-1 (FATP-1) activation are reported in this paper. Compounds 1 and 3 were the most active in the in vitro PTP-1B inhibition assay, showing IC50s of approximately 44 μM. Treatment of adipocytes with compound 1 increased the mRNA expression of PPARγ and GLUT-4 by 8- and 3-fold, respectively. Moreover, both compounds (1 and 3) also increased the relative mRNA expression of PPARα (by 8-fold) and FATP-1 (by 15-fold). Molecular docking studies were performed in order to elucidate the polypharmacological binding mode of the most active compounds on these targets. Finally, a murine model of hyperglycemia was used to evaluate the in vivo effectiveness of compounds 1 and 3. We found that both compounds are orally active using an exploratory dose of 100 mg/kg, decreasing the blood glucose concentration in an oral glucose tolerance test and a non-insulin-dependent diabetes mellitus murine model. In conclusion, we demonstrated that both molecules showed strong in vitro and in vivo effects and can be considered polypharmacological antidiabetic candidates.