Sparsentan (RE-021) stands out as a potent dual antagonist for both angiotensin II and endothelin A receptors, with inhibition constants (Kis) of 0.8 and 9.3 nM respectively[1].
体内研究
Sparsentan (RE-021) effectively blocks angiotensin II-induced blood pressure increases, with an effective dose (ED50) of 0.8 µmol/kg when administered intravenously and 3.6 µmol/kg orally. Additionally, Sparsentan has shown effectiveness and a prolonged action in the big ET-1-induced pressor model, significantly reducing blood pressure at the lowest dose tested (10 µmol/kg/day) in spontaneously hypertensive rats. It exhibits favorable oral bioavailability across various species—rats, dogs, and monkeys—with bioavailability percentages averaging 40%, 86%, and 21%, respectively. At a dosage of 100 µmol/kg/day, Sparsentan can reduce blood pressure significantly, effectively normalizing blood pressure levels in spontaneously hypertensive rats over its pharmacokinetic duration[1].
Sparsentan 细胞实验
Cell Line
Concentration
Treated Time
Description
References
Pituitary GH3 cells
0.3–100 µM
40 ms
Sparsentan differentially inhibited the peak and late components of voltage-gated Na+ current (INa). The IC50 values for peak and late INa were 15.04 μM and 1.21 μM, respectively.
Biomedicines. 2021 Dec 31;10(1):86.
Sparsentan 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Mice
FSGS model
Oral
120 mg/kg
Daily for 6 weeks
Sparsentan significantly improved glomerular hemodynamics and GFB function, including reduced podocyte calcium levels, increased afferent and efferent arteriole diameters, improved single-nephron glomerular filtration rate and glomerular capillary blood flow, and reduced proteinuria.
JCI Insight. 2024 Sep 3;9(19):e177775
Mice
FSGS, DKD, LN models
Oral
30 mmol/kg
Three times weekly
Sparsentan reduces CD8+ TRM cell responses by intervening IL-15 signaling, ameliorating podocyte injury and glomerulosclerosis
Mol Ther. 2022 Aug 3;30(8):2746-2759
GddY mice
Spontaneous IgAN Mice model
Dietary administration
900 or 1800 ppm (in diet)
From 4 weeks old to 12 or 20 weeks old, lasting 8 or 16 weeks
Evaluate the efficacy of Sparsentan in the IgAN model, results showed Sparsentan reduced ACR more rapidly and significantly than losartan, and protected glomeruli and podocytes.
Nephrol Dial Transplant. 2024 Aug 30;39(9):1494-1503
Mice
COL4A3−/− Mice model
Oral gavage
120 mg/kg
Once daily, from 3-7 weeks or 5-7 weeks of age
Sparsentan significantly delayed onset of glomerulosclerosis, interstitial fibrosis, proteinuria, and glomerular filtration rate decline. Sparsentan attenuated glomerular basement membrane defects, blunted mesangial filopodial invasion into the glomerular capillaries, increased lifespan more than losartan, and lessened changes in profibrotic/proinflammatory genes pathways in both the glomerular and renal cortical compartments. Notably, treatment with sparsentan, but not losartan, prevented accumulation of extracellular matrix in the strial capillary basement membranes in the inner ear and reduced susceptibility to hearing loss.
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