SAR247799

SAR247799 (S1P1 agonist 3) is an oral activity, selective G-protein-biased sphingosine-1 phosphate receptor-1 (S1P1 ) agonist, with EC 50 s rang from 12.6 to 493 nM in S1P1-overexpressing cells and HUVECs. SAR247799 can be used for the research of endothelial protection, including type-2 diabetes, metabolic syndrome In Vitro SAR247799 (0, 0.003, 0.01, 0.03, 0.1, 0.3, 1, 3, 10 μM; 10 min) induces a concentration-dependent phosphorylation of extracellular-regulated kinase-1/2 (Erk1/2) and protein kinase B (Akt) in HUVECs. SAR247799 (0-10 μM, 8 min) induces impedance change in HUVECs in a dose-dependent manner. SAR247799 (1 μM, 1st) does not cause desensitization demonstrated by Ca 2+ flux assay in S1P1-Chinese hamster ovary (CHO) cells. MCE has not independently confirmed the accuracy of these methods. They are for reference only. In Vivo SAR247799 (1 and 3 mg/kg; p.o.; 1 h before renal occlusion) dose dependently reduces the severity of ischemia/reperfusion (I/R)–induced acute kidney injury . SAR247799 (0.3, 1, 3 mg/kg; i.v.) dose dependently increases the coronary conductance ratio in pig model of coronary endothelial dysfunction . SAR247799 (30-min intravenous administration; 8- to 10-week-old farm pig) exposure (C max and AUC) increases with dose in pigs. Pharmacokinetic parameters : Dose (mg/kg) N C max (g/mL) T max (h) T last (h) AUC 0-last (g.h/mL) Cl (L/h/kg) Vss (L/kg) T 1/2z (h) 1 4 2.08 (8) 0.5 [0.5] [8-48] 11.8 (46) 0.113 (75) 0.516 (11) 5.62 (57) 3 7 8.10 (12) 0.5 [0.5] [24-72] 42.2 (23) 0.0754 (30) 0.446 (16) 6.21 (28) 10 3 36.7 (5) 0.5 [0.5-0.75] 72 294 (13) 0.0343 (13) 0.338 (7) 7.73 (8) 30 6 112 (27) 0.5 [0.5- 1.0] [48-72] 908 (16) 0.0338 (18) 0.294 (11) 7.35 (11) Mean values with (CV%) except T max , which is expressed as median value with [range] and Tlast as [range]. C max , maximum concentration. T max , time at which maximum concentration achieved. T last , last time point sampled. AUC 0-last , area under curve from 0 to last time point. Cl, clearance. Vss, volume at steady state or volume of distribution. T 1/2z , elimination half-life. N, number of animals. MCE has not independently confirmed the accuracy of these methods. They are for reference only. Animal Model: Acute kidney injury rats (12 to 15-week-old Fischer rats) Dosage: 1 and 3 mg/kg Administration: P.o.; administered 1 hour before renal occlusion. Result: Inhibited the increase in serum creatinine (89 and 96% at 1 and 3 mg/kg) and urea (61 and 85% at 1 and 3 mg/kg). Protected renal proximal tubules against necrosis and blunted the development of interstitial hemorrhage. Animal Model: Acute kidney injury rats (8- to 12-week-old Fischer rats) Dosage: 3 mg/kg Administration: P.o.; twice a day for 7 days and twice a day for 7 day Result: Showed a dosedependent trend for reducing macrophage. Form:Solid IC50& Target:S1PR1 12.6-493 nM (EC 50 )

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