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YM758  

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包装规格：1mg in glass bottle
产品描述：基本信息 产品编号： Y10044 产品名称： YM758 CAS: 312752-85-5   储存条件 粉末 -20℃ 四年 分子式： C26H32FN3O4 溶于液体 -80℃ 一年 分子量： 469.55     化学名：    Solubility (25°C)：   体外:   DMSO   Ethanol   Water   体内(现配现用):   ＜1mg/ml表示微溶或不溶。 普西唐提供的所有化合物浓度为内部测试所得，实际溶液度可能与公布值有所偏差，属于正常的批间细微差异现象。 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；⼀旦配成溶液，请分装保存，避免反复冻融造成的产品失效。   生物活性 产品描述 一个特异性的窦房结If电流抑制剂。 靶点 I f channel   体外研究 The inhibitory effect of YM758 on [3H]MPP uptake via human/rat organic cation transporters (hOCT1/rOct1) is investigated.YM758 inhibits rOct1- and hOCT1-mediated [3H]MPP uptake in a concentration-dependent manner with IC50 values of 23.8 and 40.5μM,respectively.The IC50 value of YM758 for [14C]Metformin uptake via rOct1 may be estimated below 10μM in the same way,whereas that is much smaller than that for [3H]MPP uptake.In addition,the inhibitory effect of YM758 on [3H]E2 17βG uptake via OATP1B1 and OATP1B3 is investigated.YM758 inhibits OATP1B1-mediated [3H]E217βG uptake in a concentration-dependent manner with a IC50 value of 13.0μM.YM758 has no inhibitory effect on OATP1B3-mediated [3H]E2 17βG uptake. 体内研究 After a single intravenous administration of 0.03,0.1,and 0.3mg/kg to tachycardia-induced beagles,YM758 plasma concentrations rapidly decrease with t1/2 values of 1.62,4.93,and 1.63h,respectively.At the corresponding doses,the CLtot values amount to 1.71,1.69,and 1.48L/h/kg,and Vdss values are 3.19,5.78,and 2.94L/kg,respectively.Because the plasma concentration 24h after administration is quantified only in the 0.1mg/kg dosing group,the larger values of t1/2 and Vdss are obtained compared with those in other dosing groups.The PK profile of YM758 in tachycardia-induced dogs appeares to be linear within the dose range of 0.03 to 0.3mg/kg.The CLtot of YM758 in the blood basis (CLb,dog) is estimated to be 1.47 to 1.69L/h/kg.The radioactivity in the rat eyeballs after dosing 14C-YM758 is extracted with a mixture of 2 mol/L hydrochloric acid and Methanol (5:95,v/v);the radioactivity recovery is 97.1% at 4h and 67.1% at 24h.The HPLC recovery of radioactivity from the extracted samples is 90.6 and 100.6% at 4 and 24h,respectively.In the eyeball at 4h after administration,YM758 (the unchanged drug) is the main compound detected (66.7%),and the metabolites YM-252124 (14.5%),YM-394111 (2.4%),and YM-234903 (1.8%) are also observed.   推荐实验方法(仅供参考) 激酶实验： Transporter-expressing or vector-transfected HEK293 cells are grown in DMEM supplemented with 10% FBS and 1% penicillin-streptomycin (v/v) and 100μg/mL Zeocin at 37℃ in an atmosphere of 5% CO2 and 95% humidity.The cells are subcultured in a medium containing 0.05% trypsin-EDTA solution.Cells are then seeded in poly-D-lysine-coated 12-wel plates at a density of 1.2×105 cells/well.For the transport study,the cell culture medium is replaced with culture medium supplemented with 5mM sodium-butyrate for 24h before the transport assay to induce the expression level of hOCT1,rOct1,OATP1B1,and OATP1B3.The transport study is performed.Uptake is initiated by adding Krebs-Henseleit buffer containing radiolabeled substrates (0.6nM [3H]MPP,10μM[14C]Metformin,20nM [3H]E217βG,or 10μM [14C]YM758) after the cells have been washed twice and preincubated with Krebs-Henseleit buffer at 37℃ for 15 min.In the concentrationdependent uptake and/or inhibition studies,the cells are incubated further in the presence of YM758 (1-1000μM).The Krebs-Henseleit buffer consists of 2.0mg/mL D-glucose,0.141mg/mL Magnesium sulfate,0.16mg/mL Potassium phosphate monobasic,0.35mg/mL Potassium chloride,6.9mg/mL Sodium chloride,0.373mg/mL Calcium chloride dihydrate,1.5mg/mL HEPES,and 2.1mg/mL Sodium bicarbonate.The pH of this solution is adjusted to 7.4 with Sodium hydroxide.The uptake is terminated at the designated time by adding ice cold Krebs-Henseleit buffer after removing the incubation buffer.The cells then are washed twice with 1mL of ice-cold Krebs-Henseleit buffer,solubilized in 0.5mL of 1.0 M Sodium hydroxide,and kept overnight at 4℃.Aliquots (0.5mL) are transferred to scintillation vials after adding 0.25mL of 2.0M hydrochloric acid.The radioactivity associated with the cells and incubation buffer is measured in a liquid scintillation counter after adding 5mL of scintillation fluid to the scintillation vials.The remaining cell lysate is used to determine the protein concentration by the method of Lowry,with bovine serum albumin as the standard.   动物实验:   Beagle Four male beagles (11.0-15.0kg) are used for the intravenous administration study.Heart rate (HR) (beats/min) is determined by doubling the number of the QRS complexes on the ECG recorded for 30 s.First,HR is measured at rest and just after initiation of tachycardia induced by intravenous Isoproterenol (0.1μg/kg) administration,and then YM758,which is dissolved in saline,is intravenously administered at doses of 0.03,0.1,and 0.3mg/kg.At 0.1,0.25,0.5,1,2,3,4,5,6,7,8,and 24h after the YM758 administration,HR is measured just after intravenous isoproterenol (0.1μg/kg) to induce tachycardia,following the measurement of resting HR at each designated point.This is followed by a minimum 1-week washout period between each study period. Blood samples (approximately 3.0mL) are withdrawn from the vein using a heparin-treated syringe,and the electrocardiogram (ECG) is recorded at the times designated (0.1,0.25,0.5,1,2,3,4,5,6,7,8,and 24h after administration).Plasma is obtained by centrifugation of the blood samples at 1870g for 15 min at 4℃ and then stored at -20℃ until determination of the YM758 concentrations. Rats Male Long-Evans rats (7 weeks) and Sprague-Dawley rats (9 weeks) are used.3mg/2.57 MBq/10mL/kg is given to rats orally by gavage using a syringe with a gastric tube.The nonalbino rats are sacrificed by ether overdose 4 and 24h after a single oral administration of 3mg/kg 14C-YM758.The fur is then rapidly clipped off,and the nasal cavity and anus are filled with 4% carboxymethylcellulose-Na.The carcass is frozen in a dry ice-acetone mixture,and the forelimbs,hind limbs,and tail are surgically removed.
保存条件：-20℃

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