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YM758 Sale

目录号 : GC32501

YM758是一个特异性的窦房结If电流抑制剂。

YM758 Chemical Structure

Cas No.:312752-85-5

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实验参考方法

Kinase experiment:

Transporter-expressing or vector-transfected HEK293 cells are grown in DMEM supplemented with 10% FBS and 1% penicillin-streptomycin (v/v) and 100 μg/mL Zeocin at 37°C 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-well 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 5 mM sodium-butyrate for 24 h 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 (0.6 nM [3H]MPP, 10 μM[14C]Metformin, 20 nM [3H]E217βG, or 10 μM [14C]YM758) after the cells have been washed twice and preincubated with Krebs-Henseleit buffer at 37°C for 15 min. In the concentration-dependent uptake and/or inhibition studies, the cells are incubated further in the presence of YM758 (1-1000 μM). The Krebs-Henseleit buffer consists of 2.0 mg/mL D-glucose, 0.141 mg/mL Magnesium sulfate, 0.16 mg/mL Potassium phosphate monobasic, 0.35 mg/mL Potassium chloride, 6.9 mg/mL Sodium chloride, 0.373 mg/mL Calcium chloride dihydrate, 1.5 mg/mL HEPES, and 2.1 mg/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 1 mL of ice-cold Krebs-Henseleit buffer, solubilized in 0.5 mL of 1.0 M Sodium hydroxide, and kept overnight at 4°C. Aliquots (0.5 mL) are transferred to scintillation vials after adding 0.25 mL of 2.0 M hydrochloric acid. The radioactivity associated with the cells and incubation buffer is measured in a liquid scintillation counter after adding 5 mL 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[1].

Animal experiment:

Beagle[2]Four male beagles (11.0-15.0 kg) 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 (0.1 μg/kg) administration, and then YM758, which is dissolved in saline, is intravenously administered at doses of 0.03, 0.1, and 0.3 mg/kg. At 0.1, 0.25, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, and 24 h after the YM758 administration, HR is measured just after intravenous isoproterenol (0.1 μg/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 3.0 mL) 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 24 h after administration). Plasma is obtained by centrifugation of the blood samples at 1870g for 15 min at 4°C and then stored at -20°C until determination of the YM758 concentrations[2].Rats[3]Male Long-Evans rats (7 weeks) and Sprague-Dawley rats (9 weeks) are used. 3 mg/2.57 MBq/10 mL/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 24 h after a single oral administration of 3 mg/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[3].

References:

[1]. Umehara K, et al. Hepatic uptake and excretion of (-)-N-{2-[(R)-3-(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)piperidino]ethyl}-4-fluorobenzamide (YM758), a novel if channel inhibitor, in rats and humans. Drug Metab Dispos. 2008 Jun;36(6):1030-8.
[2]. Umehara K, et al. Relationship between exposure of (-)-N-{2-[(R)-3-(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)piperidino]ethyl}-4-fluorobenzamide (YM758), a "funny" if current channel inhibitor, and heart rate reduction in tachycardia-induced beagle dogs. Drug Metab Dispos. 2009 Jul;37(7):1427-33.
[3]. Umehara K, et al. Investigation of long-term retention of unchanged (-)-N-{2-[(R)-3-(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)piperidino]ethyl}-4-fluorobenzamide, a novel "funny" If current channel inhibitor, and its metabolites in the eyeball and thoracic aorta of rats. Drug Metab Dispos. 2009 Nov;37(11):2137-44.

产品描述

YM758 is a "funny" If current channel (If channel) inhibitor.

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 40.5 μM, respectively. The IC50 value of YM758 for [14C]Metformin uptake via rOct1 may be estimated below 10 μM in the same way, whereas that is much smaller than that for [3H]MPP uptake. In addition, the inhibitory effect of YM758 on [3H]E217βG uptake via OATP1B1 and OATP1B3 is investigated. YM758 inhibits OATP1B1-mediated [3H]E217βG uptake in a concentration-dependent manner with a IC50 value of 13.0 μM. YM758 has no inhibitory effect on OATP1B3-mediated [3H]E217βG uptake[1].

After a single intravenous administration of 0.03, 0.1, and 0.3 mg/kg to tachycardia-induced beagles, YM758 plasma concentrations rapidly decrease with t1/2 values of 1.62, 4.93, and 1.63 h, respectively. At the corresponding doses, the CLtot values amount to 1.71, 1.69, and 1.48 L/h/kg, and Vdss values are 3.19, 5.78, and 2.94 L/kg, respectively. Because the plasma concentration 24 h after administration is quantified only in the 0.1 mg/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 0.3 mg/kg. The CLtot of YM758 in the blood basis (CLb,dog) is estimated to be 1.47 to 1.69 L/h/kg[2]. 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 4 h and 67.1% at 24 h. The HPLC recovery of radioactivity from the extracted samples is 90.6 and 100.6% at 4 and 24 h, respectively. In the eyeball at 4 h 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[3].

[1]. Umehara K, et al. Hepatic uptake and excretion of (-)-N-{2-[(R)-3-(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)piperidino]ethyl}-4-fluorobenzamide (YM758), a novel if channel inhibitor, in rats and humans. Drug Metab Dispos. 2008 Jun;36(6):1030-8. [2]. Umehara K, et al. Relationship between exposure of (-)-N-{2-[(R)-3-(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)piperidino]ethyl}-4-fluorobenzamide (YM758), a "funny" if current channel inhibitor, and heart rate reduction in tachycardia-induced beagle dogs. Drug Metab Dispos. 2009 Jul;37(7):1427-33. [3]. Umehara K, et al. Investigation of long-term retention of unchanged (-)-N-{2-[(R)-3-(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)piperidino]ethyl}-4-fluorobenzamide, a novel "funny" If current channel inhibitor, and its metabolites in the eyeball and thoracic aorta of rats. Drug Metab Dispos. 2009 Nov;37(11):2137-44.

Chemical Properties

Cas No. 312752-85-5 SDF
Canonical SMILES O=C([C@H]1CN(CCC1)CCNC(C2=CC=C(F)C=C2)=O)N3CC4=CC(OC)=C(OC)C=C4CC3
分子式 C26H32FN3O4 分子量 469.55
溶解度 Soluble in DMSO 储存条件 Store at -20°C
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1 mM 2.1297 mL 10.6485 mL 21.297 mL
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10 mM 0.213 mL 1.0648 mL 2.1297 mL
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Research Update

Investigation of Metabolite Profile of YM758, a Novel If Channel Inhibitor

Drugs R D 2016 Jun;16(2):205-16.PMID:27028751DOI:10.1007/s40268-016-0130-3.

Background: YM758 monophosphate is a novel If channel inhibitor that has an inhibitory action for If current and shows a strong and specific activity, selectively lowering the heart rate and decreasing oxygen consumption by heart muscle. Objectives: The objectives of the current study were to investigate the in vivo metabolic profiles of YM758 in mice, rats, rabbits, dogs, and monkeys and to elucidate the structures of YM758 metabolites. Methods: Biological samples were analyzed by liquid chromatography hyphenated with a radiometric detection system and liquid chromatography coupled with a mass spectrometer to clarify their metabolic patterns. To elucidate their structures, metabolites were isolated and analyzed by mass spectrometry and nuclear magnetic resonance spectroscopy. Results: Our results from in vivo metabolic profiling in humans and animals indicated there is no significant species difference in the metabolism of YM758, and the metabolic pathways of YM758 are considered to be oxidation, hydration, and demethylation followed by sulfate or glucuronide conjugation.

Hepatic uptake and excretion of (-)-N-{2-[(R)-3-(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)piperidino]ethyl}-4-fluorobenzamide (YM758), a novel if channel inhibitor, in rats and humans

Drug Metab Dispos 2008 Jun;36(6):1030-8.PMID:18332079DOI:10.1124/dmd.108.020669.

(-)-N-{2-[(R)-3-(6,7-Dimethoxy-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)piperidino]ethyl}-4-fluorobenzamide (YM758), a novel "funny" If current channel (If channel) inhibitor, is being developed as a treatment for stable angina and atrial fibrillation. The hepatic uptake/excretion of YM758 was clarified using transporter-expressing mammalian cells and hepatocytes mainly in humans and partly in rats. cDNA-expressing human embryonic kidney 293 cells were used to determine that YM758 was greatly taken up via organic anion-transporting polypeptide (OATP) 1B1 and slightly via human organic cation transporter (hOCT) 1/rat organic cation transporter 1 but not via OATP1B3. In addition, the uptake of 17beta-estradiol-d-17beta-glucuronide via OATP1B1 was inhibited in the presence of YM758, whereas that via OATP1B3 was not. In contrast, time-dependent uptake of YM758 into rat/human hepatocytes at 37 degrees C was observed, as was concentration-dependent uptake into human hepatocytes (K(m) value of 87.9 microM). This saturable uptake of YM758 into human hepatocytes was inhibited in the presence of quinidine (an inhibitor for OATP1B1) but not cimetidine (an inhibitor for the hOCT family). Moreover, the permeation clearance ratios for the transcellular transport of YM758 across multidrug resistance (MDR) 1-expressing LLC-PK1 cells were extensively higher than those across LLC-PK1 cells, which indicate that MDR1-mediated transport is one of the possible pathways through which YM758 may be excreted into the bile. These results indicate that YM758 is taken up into hepatocytes mainly via OATP1B1, but not via hOCT1, and is excreted into the bile via MDR1 in humans; however, passive diffusion or an unknown uptake/excretion mechanism could be at work in the hepatocytes. This study is the first to clarify the saturable hepatic uptake and/or the excretion mechanism by the If channel inhibitor.

Comparative evaluation of absorption, distribution, and excretion of YM758, a novel If channel inhibitor, between albino and non-albino rats

Xenobiotica 2008 May;38(5):527-39.PMID:18421625DOI:10.1080/00498250801995788.

1. YM758 is a novel If channel inhibitor for the treatment of stable angina and atrial fibrillation. The absorption, distribution, and excretion of YM758 have been investigated in albino and non-albino rats after a single oral administration of (14)C-YM758 monophosphate. 2. YM758 was well absorbed from all segments of the gastrointestinal tract except for the stomach. After oral administration, the ratio of AUC(0-1 h) between the plasma concentrations of radioactivity and the unchanged drug was estimated to be 17.7%, which suggests metabolism. 3. The distribution of the radioactivity derived from (14)C-YM758 in tissues was evaluated both in albino and non-albino rats. The radioactivity concentrations in most tissues were higher than those in plasma, which indicates that the radioactivity is well distributed to tissues. Extensive accumulation and slower elimination of radioactivity were noted in the thoracic aorta of albino and non-albino rats as well as in the eyeballs of non-albino rats. The recovery rates of radioactivity in urine and bile after oral dosing to bile duct-cannulated albino rats were 17.8% and 57.3%, respectively. 4. These results suggest that YM758 was extensively absorbed, subjected to metabolism, and excreted mainly into the bile after oral administration to rats, and extensive accumulation of the unchanged drug and/or metabolites into tissues such as the thoracic aorta and eyeballs was observed.

Relationship between exposure of (-)-N-{2-[(R)-3-(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)piperidino]ethyl}-4-fluorobenzamide (YM758), a "funny" if current channel inhibitor, and heart rate reduction in tachycardia-induced beagle dogs

Drug Metab Dispos 2009 Jul;37(7):1427-33.PMID:19359407DOI:10.1124/dmd.108.026385.

(-)-N-{2-[(R)-3-(6,7-Dimethoxy-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)piperidino]ethyl}-4-fluorobenzamide (YM758), a novel "funny" If current channel (If channel) inhibitor, is developed as a treatment for stable angina and atrial fibrillation. In this study, the pharmacokinetic/pharmacodynamic (PK/PD) relationship after intravenous administration of YM758 to tachycardia-induced dogs was investigated and described based on the simplified compartment model. The PK of YM758 in dogs did not differ between the nontreated and tachycardia-induced groups. A drug-induced reduction in heart rate (HR) was clearly observed, and the half-life of the duration of the effect (approximately 4.0 h) was longer than that of the plasma concentration of the unchanged drug. The fitting and simulation procedure from the PK/PD relationship between the time profiles for YM758 plasma concentration and HR reduction had an ECe(50) value (YM758 concentration in the effective compartment resulting in a 50% decrease of the maximum effect) of 6.0 ng/ml, which did not agree with the results of the in vitro experiment using right atria isolated from guinea pigs (EC(30), 70.4 ng/ml). In addition, in the in vitro experiments, YM758 metabolites had a weak inhibitory effect, if any, on the spontaneous beat rate of the right atria from guinea pigs. These data, along with the previous finding that YM758 and its metabolites are eliminated rapidly from rat hearts, indicate that the duration of the pharmacological effect of YM758 (compared with the rapid elimination of the plasma drug concentration) may be the result of strong binding and/or slower dissociation of YM758 in the If channel. Such PK/PD analyses allow the pharmacological profiles of many drugs, especially cardiovascular drugs, to be more readily understood and better predicted during the clinical stages.

Evaluation of the inhibitory and induction potential of YM758, a novel If channel inhibitor, for human P450-mediated metabolism

Eur J Drug Metab Pharmacokinet 2008 Oct-Dec;33(4):211-23.PMID:19230594DOI:10.1007/BF03190875.

This study was designed to examine the in vitro metabolism of YM758, a novel cardiovascular agent, and to evaluate its potential to cause drug interactions and induction of CYP isozymes. After incubation with pooled human liver microsomes, YM758 was converted to two major metabolites (AS2036313-00, and YM-394111 or YM-394112). The formation of AS2036313-00, and YM-394111 or YM-394112 were mediated by CYP2D6 and CYP3A4, respectively, which was elucidated by using a bank of human liver microsomes and recombinant CYP enzymes in combination with the utilization of typical substrates and inhibitors. The Ki values of YM758 for midazolam, nifedipine, and metoprolol metabolism ranged from 59 to 340 microM, being much higher than the YM758 concentration in human plasma. The formation of AS2036313-00, and YM-394111 or YM-394112 was inhibited by quinidine and ketoconazole with Ki values of 140 and 0.24 microM, respectively, which indicates that YM758 metabolism may be affected by coadministration of strong CYP2D6 and 3A4 inhibitors in vivo, given the clinical plasma concentrations of quinidine and ketoconazole. After human hepatocytes were exposed to 10 microM YM758, microsomal activity and mRNA level for CYP1A2 were not induced while those for CYP3A4 were slightly induced. The tested concentration was much higher than that in human plasma, which suggests that the induction potential of YM758 is also negligible.