Research output: Contribution to journal › Article › peer-review
Antidiabetic Effect of Dihydrobetulonic Acid Derivatives as Pparα/γ Agonists. / Khvostov, Mikhail V.; Blokhin, Mikhail E.; Borisov, Sergey A. et al.
In: Scientia Pharmaceutica, Vol. 92, No. 4, 65, 05.12.2024.Research output: Contribution to journal › Article › peer-review
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TY - JOUR
T1 - Antidiabetic Effect of Dihydrobetulonic Acid Derivatives as Pparα/γ Agonists
AU - Khvostov, Mikhail V.
AU - Blokhin, Mikhail E.
AU - Borisov, Sergey A.
AU - Fomenko, Vladislav V.
AU - Meshkova, Yulia V.
AU - Zhukova, Natalia A.
AU - Nikonova, Sophia V.
AU - Pavlova, Sophia V.
AU - Pogosova, Maria A.
AU - Medvedev, Sergey P.
AU - Luzina, Olga A.
AU - Salakhutdinov, Nariman F.
N1 - Финансирующий спонсор: Russian Science Foundation 24-25-00120
PY - 2024/12/5
Y1 - 2024/12/5
N2 - 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.
AB - 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.
KW - dihydrobetulonic acid
KW - dual PPARα/γ agonists
KW - hypoglycemic activity
KW - type 2 diabetes mellitus
KW - dihydrobetulonic acid
KW - dual PPARα/γ agonists
KW - hypoglycemic activity
KW - type 2 diabetes mellitus
UR - https://www.mendeley.com/catalogue/510136f8-7a01-3032-a2f4-3464b7de49fe/
UR - https://www.scopus.com/record/display.uri?eid=2-s2.0-85213542242&origin=inward&txGid=c8757a49bf8612cded97aad39e670cad
U2 - 10.3390/scipharm92040065
DO - 10.3390/scipharm92040065
M3 - Article
VL - 92
JO - Scientia Pharmaceutica
JF - Scientia Pharmaceutica
SN - 2218-0532
IS - 4
M1 - 65
ER -
ID: 61407605