Fimasartan

Fimasartan是一种非肽段的angiotensin II receptor拮抗剂，与AT1受体非竞争性地结合。用于高血压和心力衰竭的治疗中。

IC50& Target

体外

Fimasartan is a selective AT1 receptor antagonist. The concentration that inhibits the binding of [125I]Ang II to the AT1 receptor from rat adrenal cortex by 50% (IC50) is 0.13 nM. Fimasartan shows superior inhibitory activity in the contraction of isolated rabbit thoracic aorta compared to other ARBs such as losartan and candesartan. Fimasartan potently attenuates myocardial apoptotic death in reperfused rat heart and H9c2 cells. Fimasartan could attenuate mitochondrial damage which is associated with minimizing the reduction in Bcl-2 and connected with the reduction in p53 and activation of Akt and GSK-3β, and inhibiting mitochondrial Ca2+ overload by suppressing the ICa,Land MCU.

体内

In various animal models including renal hypertensive rats, spontaneously hypertensive rats and Beagle dogs, fimasartan effectively reduces blood pressure in a dose-dependent manner following single or repeated oral and intravenous administration. Fimasartan does not affect general behavior, respiratory rate or tidal volume in experimental animals, and shows no adverse findings in the human ether-a-go-go-related gene (hERG) test or monkey telemetry study. A number of general toxicity, carcinogenic toxicity, genetic toxicity, and developmental toxicity studies given either orally or intravenously in various species including mice, rats, monkeys and dogs are conducted and these preclinical results demonstrate the safety and tolerability of fimasartan for long-term clinical use and offer sufficient safety margins to support the expected human therapeutic dose. Fimasartan is rapidly absorbed following oral administration with the time to peak plasma concentration (Tmax) ranging 0.5-3 h and the terminal half-life (t1/2) being 5-16 h at doses of 20 to 480 mg in healthy subjects. Similar results are obtained in patients with hypertension, i.e., Tmax ranges 0.5-1.3 h and t1/2is 7-10 h following fimasartan administration at doses 20-180 mg in the subsequent phase II study. The urinary excretion of fimasartan is low, with the overall urinary excretion of unchanged drug over the first 24 h after dosing being less than 3% of the administered dose. Fimasartan undergoes nonrenal elimination with minimal metabolism. Fimasartan treatment before myocardial ischemia significantly attenuates reperfusion .injury and apoptotic changes, possibly by suppressing mitochondrial damage during reperfusion In various preclinical studies, including aortic balloon injury, myocardial infarct ischemia/reperfusion, doxorubicin cardiotoxicity, and ischemic stroke models, fimasartan shows anti-inflammatory and organ-protecting effects.

Enalapril Maleate

MB1578

Losartan Potassium

MB2800

Eprosartan mesylate

1 mg

5 mg

10 mg

1 mM

1.9934 mL

9.9671 mL

19.9342 mL

5 mM

0.3987 mL

1.9934 mL

3.9868 mL

10 mM

0.1993 mL

0.9967 mL

1.9934 mL

50 mM

0.0399 mL

0.1993 mL

0.3987 mL