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| ln Vitro |
It was investigated how YM758 inhibited the rat/human organic cation transporter (hOCT1/rOct1)'s ability to absorb [3H]MPP. YM758 exhibits concentration-dependent inhibition of rOct1- and hOCT1-mediated [3H]MPP uptake, with IC50 values of 23.8 and 40.5 μM, respectively. Similar to the IC50 value for [3H]MPP uptake, the IC50 value for YM758 uptake of [14C]metformin via rOct1 can be estimated to be below 10 μM. Furthermore, YM758's inhibitory effect on [3H]E217βG uptake through OATP1B1 and OATP1B3 was investigated. With an IC50 value of 13.0 μM, YM758 inhibits [3H]E217βG uptake mediated by OATP1B1 in a concentration-dependent manner. The uptake of [3H]E217βG mediated by OATP1B3 is not inhibited by YM758 [1].
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| ln Vivo |
YM758 plasma concentrations dropped quickly in beagles with tachycardia following a single intravenous dose of 0.03, 0.1, and 0.3 mg/kg; the corresponding t1/2 values were 1.62, 4.93, and 1.63 hours. The Vdss values were 3.19, 5.78, and 2.94 L/kg, while the CLtot values were 1.71, 1.69, and 1.48 L/h/kg at the corresponding doses. Greater t1/2 and Vdss values were obtained in comparison to other administration groups because the 0.1 mg/kg administration group only had blood drug concentration measured 24 hours after treatment. In dogs with tachycardia, the PK profile of YM758 seems to be linear between 0.03 and 0.3 mg/kg. On a blood basis (CLb, dog), the CLtot of YM758 is predicted to be 1.47 to 1.69 L/h/kg [2]. After administering 14C-YM758, extract radioactivity from rat eyeballs using a solution of 2mol/L hydrochloric acid and methanol (5:95, v/v); the radioactivity recovery rate was 67.1% after 24 hours and 97.1% after 4 hours. After 4 hours and 24 hours, respectively, the extracted samples' radioactive HPLC recoveries were 90.6% and 100.6%. Four hours after delivery, the primary molecule found in the eyes was YM758, the initial medication, accounting for 66.7% of the sample. Additionally, the metabolites YM-252124 (14.5%), YM-394111 (2.4%), and YM-234903 (1.8%) were noted [3].
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| 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 Ju
[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 tachyca [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 |
| Molecular Formula |
C26H32FN3O4
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|---|---|
| Molecular Weight |
469.548390388489
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| Exact Mass |
469.237
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| CAS # |
312752-85-5
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| PubChem CID |
9894205
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| Appearance |
Typically exists as solid at room temperature
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| Density |
1.2±0.1 g/cm3
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| Boiling Point |
680.5±55.0 °C at 760 mmHg
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| Flash Point |
365.3±31.5 °C
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| Vapour Pressure |
0.0±2.1 mmHg at 25°C
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| Index of Refraction |
1.571
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| LogP |
3.13
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
6
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| Rotatable Bond Count |
7
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| Heavy Atom Count |
34
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| Complexity |
687
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| Defined Atom Stereocenter Count |
1
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| SMILES |
O=C([C@H]1CN(CCC1)CCNC(C2=CC=C(F)C=C2)=O)N3CC4=CC(OC)=C(OC)C=C4CC3
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| InChi Key |
MWLKUSHZNSYRKK-HXUWFJFHSA-N
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| InChi Code |
InChI=1S/C26H32FN3O4/c1-33-23-14-19-9-12-30(17-21(19)15-24(23)34-2)26(32)20-4-3-11-29(16-20)13-10-28-25(31)18-5-7-22(27)8-6-18/h5-8,14-15,20H,3-4,9-13,16-17H2,1-2H3,(H,28,31)/t20-/m1/s1
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| Chemical Name |
N-[2-[(3R)-3-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline-2-carbonyl)piperidin-1-yl]ethyl]-4-fluorobenzamide
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO : ~100 mg/mL (~212.97 mM)
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| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.1297 mL | 10.6485 mL | 21.2970 mL | |
| 5 mM | 0.4259 mL | 2.1297 mL | 4.2594 mL | |
| 10 mM | 0.2130 mL | 1.0648 mL | 2.1297 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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