Antidiabetic Effect of Dihydrobetulonic Acid Derivatives as Pparα/γ Agonists

Antidiabetic Effect of Dihydrobetulonic Acid Derivatives as Pparα/γ Agonists Научная публикация

Журнал

Scientia Pharmaceutica
ISSN: 0036-8709 , E-ISSN: 2218-0532

Вых. Данные

Год: 2024, Том: 92, Номер: 4, Номер статьи : 65, Страниц : DOI: 10.3390/scipharm92040065

Ключевые слова

dual PPARα/γ agonists; type 2 diabetes mellitus; hypoglycemic activity; dihydrobetulonic acid

Авторы

Khvostov Mikhail V. ¹ , Blokhin Mikhail E. ¹ , Borisov Sergey A. ¹ , Fomenko Vladislav V. ¹ , Meshkova Yulia V. ¹ , Zhukova Natalia A. ¹ , Nikonova Sophia V. ² , Pavlova Sophia V. ³ , Pogosova Maria A. ³ , Medvedev Sergey P. ³ , Luzina Olga A. ¹ , Salakhutdinov Nariman F. ¹

Организации

1	N. N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences
2	V. Zelman Faculty for the Medicine and Psychology, Novosibirsk State University
3	Institute of Cytology and Genetics, Siberian Branch of Russian Academy of Sciences

Dual PPARα/γ agonists can normalize both glucose and lipid metabolism in patients with type 2 diabetes mellitus. The development of such drugs faced the detection of various toxic effects in phase III clinical trials. However, two drugs of this class managed to pass all stages of clinical trials, which makes the search for new dual PPARα/γ agonists promising. In the present study, a series of dihydrobetulonic acid amides differing in the length of the amino-alcohol linker and incorporating a pharmacophore fragment of (S)-2-ethoxy-3-phenylpropanoic acid were synthesized. The in vitro study showed that the length of the aminoalcohol linker dramatically affects the level of activation of PPAR-α and γ receptors. The synthesized compounds were tested for their ability to improve glycemic control and to counter lipid abnormalities in C57Bl/6 Ay/a mice at a dose of 30 mg/kg. Of all the compounds tested, the dihydrobetulonic acid derivative with an aminoethanol linker (15a) had the most pronounced effect in improving insulin sensitivity and glucose tolerance, and in reducing blood triglyceride levels. In addition, 15a dramatically counteracted the pathological changes in the liver, pancreas, kidney, and brown fat tissue that are characteristic of type 2 diabetes.

Khvostov M.V. , Blokhin M.E. , Borisov S.A. , Fomenko V.V. , Meshkova Y.V. , Zhukova N.A. , Nikonova S.V. , Pavlova S.V. , Pogosova M.A. , Medvedev S.P. , Luzina O.A. , Salakhutdinov N.F.
Antidiabetic Effect of Dihydrobetulonic Acid Derivatives as Pparα/γ Agonists
Scientia Pharmaceutica. 2024. V.92. N4. 65 . DOI: 10.3390/scipharm92040065 WOS OpenAlex

Поступила в редакцию:	7 окт. 2024 г.
Принята к публикации:	2 дек. 2024 г.
Опубликована в печати:	5 дек. 2024 г.
Опубликована online:	5 дек. 2024 г.

Web of science:	WOS:001387160600001
OpenAlex:	W4405075398

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