MDH2-IN-2 is an orally active MDH2 inhibitor with an IC50 of 5.9 μM. MDH2-IN-2 reduces the levels of senescence markers and senescence-associated secretory phenotype (SASP) factors in mammalian cell models. MDH2-IN-2 extends the lifespan and improves the healthspan of Caenorhabditis elegans. MDH2-IN-2 alleviates tissue senescence in aged mice, inhibits SASP factors, and restores liver and kidney functions. MDH2-IN-2 is applicable for senescence-related research [1].
In Vivo, MDH2-IN-2 (100 μM; incorporated into NGM plates; continuous exposure) extends the mean lifespan of wild-type Caenorhabditis elegans by 15.49% and improves multiple healthspan-related indicators[1]. MDH2-IN-2 (0-50 mg/kg; i.g.; once daily; 3 weeks) significantly inhibits multiple SASP factors in premature senescent male C57BL/6J mice induced by Doxorubicin [1]. MDH2-IN-2 (5-10 mg/kg; i.g.; once daily; 3 months) reverses age-related serum biochemical abnormalities, inhibits the production of SASP factors, reduces the expression of renal senescence markers, and improves renal histological morphology in naturally aged male C57BL/6J mice[1].
In Vitro, MDH2-IN-2 (Compound 28i) inhibits the activity of recombinant human MDH1 enzyme, with an IC50 value of 25.3 μM[1]. MDH2-IN-2 (1 μM; 3 days) significantly downregulates the mRNA levels of various SASP factors in MRC-5 cells, and reduces the expression level of p53 protein and the proportion of SA-β-gal-positive cells in replicatively senescent MRC-5 cells[1]. MDH2-IN-2 (1 μM) significantly reduces the proportion of SA-β-gal-positive NRK-52E cells that undergo senescence induced by Mitomycin C [1]. MDH2-IN-2 (1 μM; 5 days) significantly reduces the expression level of p16 protein and the proportion of SA-β-gal positive cells in replicative senescent MEFs[1]. MDH2-IN-2 (1 μM; 5-60 minutes) undergoes rapid metabolic turnover in both human and mouse liver microsomes, with corresponding T1/2 values of 1.15 min and 1.10 min, respectively[1].
References:
[1]. Wu L, et al. Discovery of Novel MDH2 Inhibitor 28i by Secondary Development of Glibenclamide with Potent Antiaging Activities. J Med Chem. 2026;69(3):2400-2423.
In Vivo, MDH2-IN-2 (100 μM; incorporated into NGM plates; continuous exposure) extends the mean lifespan of wild-type Caenorhabditis elegans by 15.49% and improves multiple healthspan-related indicators[1]. MDH2-IN-2 (0-50 mg/kg; i.g.; once daily; 3 weeks) significantly inhibits multiple SASP factors in premature senescent male C57BL/6J mice induced by Doxorubicin [1]. MDH2-IN-2 (5-10 mg/kg; i.g.; once daily; 3 months) reverses age-related serum biochemical abnormalities, inhibits the production of SASP factors, reduces the expression of renal senescence markers, and improves renal histological morphology in naturally aged male C57BL/6J mice[1].
In Vitro, MDH2-IN-2 (Compound 28i) inhibits the activity of recombinant human MDH1 enzyme, with an IC50 value of 25.3 μM[1]. MDH2-IN-2 (1 μM; 3 days) significantly downregulates the mRNA levels of various SASP factors in MRC-5 cells, and reduces the expression level of p53 protein and the proportion of SA-β-gal-positive cells in replicatively senescent MRC-5 cells[1]. MDH2-IN-2 (1 μM) significantly reduces the proportion of SA-β-gal-positive NRK-52E cells that undergo senescence induced by Mitomycin C [1]. MDH2-IN-2 (1 μM; 5 days) significantly reduces the expression level of p16 protein and the proportion of SA-β-gal positive cells in replicative senescent MEFs[1]. MDH2-IN-2 (1 μM; 5-60 minutes) undergoes rapid metabolic turnover in both human and mouse liver microsomes, with corresponding T1/2 values of 1.15 min and 1.10 min, respectively[1].
References:
[1]. Wu L, et al. Discovery of Novel MDH2 Inhibitor 28i by Secondary Development of Glibenclamide with Potent Antiaging Activities. J Med Chem. 2026;69(3):2400-2423.