TY - JOUR

T1 - Design and Biological Evaluation of Monoterpene-Conjugated (S)-2-Ethoxy-3-(4-(4-hydroxyphenethoxy)phenyl)propanoic Acids as New Dual PPARα/γ Agonists

AU - Borisov, Sergey A.

AU - Blokhin, Mikhail E.

AU - Meshkova, Yulia V.

AU - Marenina, Maria K.

AU - Zhukova, Nataliya A.

AU - Pavlova, Sophia V.

AU - Lastovka, Anastasiya V.

AU - Fomenko, Vladislav V.

AU - Zhurakovsky, Igor P.

AU - Luzina, Olga A.

AU - Khvostov, Mikhail V.

AU - Kudlay, Dmitry A.

AU - Salakhutdinov, Nariman F.

N1 - Design and Biological Evaluation of Monoterpene-Conjugated (S)-2-Ethoxy-3-(4-(4-hydroxyphenethoxy)phenyl)propanoic Acids as New Dual PPARα/γ Agonists / S. A. Borisov, M. E. Blokhin, Yu. V. Meshkova [et al.] // Molecules. – 2025. – Vol. 30. - No. 24. – P. 4775. – DOI 10.3390/molecules30244775. – EDN EAHYHC. This research was funded by the Russian Scientific Foundation project No. 24-25-00120.

PY - 2025/12/14

Y1 - 2025/12/14

N2 - Metabolic syndrome, a collective term for lipid and carbohydrate disorders in the organism, is the primary cause of type 2 diabetes mellitus development and its associated systemic side effects. The current approach for the medical treatment of this condition usually requires multiple medications, targeting multiple pathophysiological pathways. A promising drug class in that regard is the dual PPARα/γ agonists, which impact both lipid and carbohydrate metabolism, yet to this day the vast majority of them have not passed the clinical trials, due to potential toxicity risks. In the present study we synthesized and tested a series of monoterpene-substituted (S)-2-ethoxy-3-(4-(4-hydroxyphenethoxy)phenyl)propanoic acids as potentially effective and safe novel dual PPARα/γ agonists. In vitro studies showed that nearly all of the tested compounds were sufficiently active towards both PPARα and PPARγ. All compounds were tested in vivo, using C57BL/6 Ay/a mice with T2DM symptoms, in order to evaluate their impact on carbohydrate and lipid metabolism. The most promising of them was found to be compound 5h, containing a cumin fragment, which showed pronounced hypoglycemic activity by boosting tissue insulin sensitivity and hypolipidemic effects manifested by reductions in fat tissue mass and blood triglyceride levels, while simultaneously displaying a relatively safe profile.

AB - Metabolic syndrome, a collective term for lipid and carbohydrate disorders in the organism, is the primary cause of type 2 diabetes mellitus development and its associated systemic side effects. The current approach for the medical treatment of this condition usually requires multiple medications, targeting multiple pathophysiological pathways. A promising drug class in that regard is the dual PPARα/γ agonists, which impact both lipid and carbohydrate metabolism, yet to this day the vast majority of them have not passed the clinical trials, due to potential toxicity risks. In the present study we synthesized and tested a series of monoterpene-substituted (S)-2-ethoxy-3-(4-(4-hydroxyphenethoxy)phenyl)propanoic acids as potentially effective and safe novel dual PPARα/γ agonists. In vitro studies showed that nearly all of the tested compounds were sufficiently active towards both PPARα and PPARγ. All compounds were tested in vivo, using C57BL/6 Ay/a mice with T2DM symptoms, in order to evaluate their impact on carbohydrate and lipid metabolism. The most promising of them was found to be compound 5h, containing a cumin fragment, which showed pronounced hypoglycemic activity by boosting tissue insulin sensitivity and hypolipidemic effects manifested by reductions in fat tissue mass and blood triglyceride levels, while simultaneously displaying a relatively safe profile.

KW - dual PPARα/γ agonists

KW - hypoglycemic activity

KW - hypolipidemic activity

KW - metabolic syndrome

KW - monoterpenoids

KW - type 2 diabetes mellitus

UR - https://www.scopus.com/pages/publications/105025791923

UR - https://elibrary.ru/item.asp?id=88455686

UR - https://www.mendeley.com/catalogue/fdaafcd8-4db5-33ae-9279-8a6a60bbd234/

U2 - 10.3390/molecules30244775

DO - 10.3390/molecules30244775

M3 - Article

C2 - 41471798

VL - 30

JO - Molecules

JF - Molecules

SN - 1420-3049

IS - 24

M1 - 4775

ER -