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OR-1896 Sale

(Synonyms: 左西孟旦杂质) 目录号 : GC39415

OR-1896 是 Levosimendan 的活性长寿代谢产物。OR-1896 是一种高选择性磷酸二酯酶 (PDE III) 抑制剂,是一种功能强大的血管扩张剂。OR-1896 可以打开 ATP 敏感的 K+ 通道,并具有 Ca2+ 致敏作用。OR-1896 可减轻心肌细胞的凋亡,心脏重塑和心肌炎症。

OR-1896 Chemical Structure

Cas No.:220246-81-1

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10mM (in 1mL DMSO)
¥2,772.00
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5mg
¥2,520.00
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10mg
¥4,500.00
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25mg
¥9,900.00
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Sample solution is provided at 25 µL, 10mM.

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产品描述

OR-1896 is an active long-lived metabolite of Levosimendan. OR-1896 is a highly selective phosphodiesterase (PDE) III isoform inhibitor and a powerful vasodilator. OR-1896 can open ATP-sensitive K+ channels and has Ca2+-sensitizing effect. OR-1896 mitigates cardiomyocyte apoptosis, cardiac remodeling and myocardial inflammation[1].

[1]. Papp, Z, et al., Levosimendan: molecular mechanisms and clinical implications: consensus of experts on the mechanisms of action of levosimendan. Int J Cardiol. 2012 Aug 23;159(2):82-7.

Chemical Properties

Cas No. 220246-81-1 SDF
别名 左西孟旦杂质
Canonical SMILES CC(NC1=CC=C(C([C@H](C)C2)=NNC2=O)C=C1)=O
分子式 C13H15N3O2 分子量 245.28
溶解度 DMSO: 62.5 mg/mL (254.81 mM) 储存条件 Store at -20°C
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1 mM 4.077 mL 20.3849 mL 40.7697 mL
5 mM 0.8154 mL 4.077 mL 8.1539 mL
10 mM 0.4077 mL 2.0385 mL 4.077 mL
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Research Update

The Effects of the Levosimendan Metabolites OR-1855 and OR-1896 on Endothelial Pro-Inflammatory Responses

Biomedicines 2023 Mar 16;11(3):918.PMID:36979897DOI:10.3390/biomedicines11030918.

The calcium sensitizer levosimendan is used for the treatment of acute decompensated heart failure. A small portion (4-7%) of levosimendan is metabolized to the pharmacologically active metabolite OR-1896 via the inactive intermediate OR-1855. In addition, levosimendan has been shown to exert positive effects on the endothelium in vitro antagonizing vascular dysfunction and inflammation. However, the function of the levosimendan metabolites within this context is still unknown. In this study, we thus investigated the impact of the metabolites OR-1896 and OR-1855 on endothelial inflammatory processes in vitro. We observed a reduction of IL-1β-dependent endothelial adhesion molecule ICAM-1 and VCAM-1 as well as interleukin (IL) -6 expression upon levosimendan treatment but not after treatment with OR-1855 or OR-1896, as assessed by western blotting, flow cytometry, and qRT-PCR. Instead, the metabolites impaired IL-1β-induced ROS formation via inactivation of the MAPK p38, ERK1/2, and JNK. Our results suggest that the levosimendan metabolites OR-1896 and OR-1855 have certain anti-inflammatory properties, partly other than levosimendan. Importantly, they additionally show that the intermediate metabolite OR-1855 does, in fact, have pharmacological effects in the endothelium. This is interesting, as the metabolites are responsible for the long-term therapeutic effects of levosimendan, and heart failure is associated with vascular dysfunction and inflammation.

Metabolism of OR-1896, a metabolite of levosimendan, in rats and humans

Xenobiotica 2008 Feb;38(2):156-70.PMID:18197557DOI:10.1080/00498250701744658.

OR-1896 is a pharmacologically active, long-lived metabolite of levosimendan. In the current study, the metabolism of (14)C-labelled OR-1896 was investigated in six healthy men after intravenous infusion over 10 min and in male rats after an intravenous bolus dose. In human plasma, the only (14)C-compounds detected were (14)C-OR-1896 and its deacetylated form, (14)C-OR-1855, in varying proportions in different subjects. In rat plasma >93% of radioactivity was associated with OR-1896. Radioactivity was mainly excreted to urine in both rats (about 69% of the dose) and humans (about 87% of the dose). OR-1896 was a major urinary compound in both humans and rats. Another major human metabolite was hypothesized as N-conjugated OR-1855. Other human and rat urinary biotransformation products were characterized as N-hydroxylated OR-1896 and N-hydroxylated OR-1855, as well as glucuronide or sulphate conjugates of N-hydroxyl OR-1896. The main difference between rat and human metabolism was a lower amount of OR-1855-related metabolites in the rats. In human faecal homogenates, only OR-1896 and OR-1855 were detected, whereas rat faecal metabolite profile was similar to that in urine.

Comparative effects of levosimendan, OR-1896, OR-1855, dobutamine, and milrinone on vascular resistance, indexes of cardiac function, and O2 consumption in dogs

Am J Physiol Heart Circ Physiol 2008 Jan;294(1):H238-48.PMID:17982006DOI:10.1152/ajpheart.01181.2007.

Levosimendan enhances cardiac contractility via Ca(2+) sensitization and induces vasodilation through the activation of ATP-dependent K(+) and large-conductance Ca(2+)-dependent K(+) channels. However, the hemodynamic effects of levosimendan, as well as its metabolites, OR-1896 and OR-1855, relative to plasma concentrations achieved, are not well defined. Thus levosimendan, OR-1896, OR-1855, or vehicle was infused at 0.01, 0.03, 0.1, and 0.3 mumol.kg(-1).30 min(-1), targeting therapeutic to supratherapeutic concentrations of total levosimendan (62.6 ng/ml). Results were compared with those of the beta(1)-agonist dobutamine and the phosphodiesterase 3 inhibitor milrinone. Peak concentrations of levosimendan, OR-1896, and OR-1855 were 455 +/- 21, 126 +/- 6, and 136 +/- 6 ng/ml, respectively. Levosimendan and OR-1896 produced dose-dependent reductions in mean arterial pressure (-31 +/- 2 and -42 +/- 3 mmHg, respectively) and systemic resistance without affecting pulse pressure, effects paralleled by increases in heart rate; OR-1855 produced no effect at any dose tested. Dobutamine, but not milrinone, increased mean arterial pressure and pulse pressure (17 +/- 2 and 23 +/- 2 mmHg, respectively). Regarding potency to elicit reductions in time to peak pressure and time to systolic pressure recovery: OR-1896 > levosimendan > milrinone > dobutamine. Levosimendan and OR-1896 elicited dose-dependent increases in change in pressure over time (118 +/- 10 and 133 +/- 13%, respectively), concomitant with reductions in left ventricular end-diastolic pressure and ejection time. However, neither levosimendan nor OR-1896 produced increases in myocardial oxygen consumption at inotropic and vasodilatory concentrations, whereas dobutamine increased myocardial oxygen consumption (79% above baseline). Effects of the levosimendan and OR-1896 were limited to the systemic circulation; neither compound produced changes in pulmonary pressure, whereas dobutamine produced profound increases (74 +/- 13%). Thus levosimendan and OR-1896 are hemodynamically active in the anesthetized dog at concentrations observed clinically and elicit cardiovascular effects consistent with activation of both K(+) channels and Ca(2+) sensitization, whereas OR-1855 is inactive on endpoints measured in this study.

Pharmacokinetics and excretion balance of OR-1896, a pharmacologically active metabolite of levosimendan, in healthy men

Eur J Pharm Sci 2007 Dec;32(4-5):271-7.PMID:17888637DOI:10.1016/j.ejps.2007.08.003.

Objective: To investigate the pharmacokinetics and excretion balance of [(14)C]-OR-1896, a pharmacologically active metabolite of levosimendan, in six healthy male subjects. In addition, pharmacokinetic parameters of total radiocarbon and the deacetylated congener, OR-1855, were determined. Methods: OR-1896 was administered as a single intravenous infusion of 200 microg of [(14)C]-OR-1896 (specific activity 8.6 MBq/mg) over 10 min. The pharmacokinetic parameters were calculated by three-compartmental methods. Results: During the 14-day collection of urine and faeces, excretion (+/-S.D.) averaged 94.2+/-1.4% of the [(14)C]-OR-1896 dose. Mean recovery of radiocarbon in urine was 86.8+/-1.9% and in faeces 7.4+/-1.5%. Mean terminal elimination half-life of OR-1896 (t(1/2)) was 70.0+/-44.9 h. Maximum concentrations of OR-1855 were approximately 30% to that of OR-1896. Total clearance and the volume of distribution of OR-1896 were 2.0+/-0.4 l/h and 175.6+/-74.5l, respectively. Renal clearances of OR-1896 and OR-1855 were 0.9+/-0.4 l/h and (5.4+/-2.3)x10(-4) l/h, respectively. Conclusions: This study provides data to demonstrate that nearly one half of OR-1896 is eliminated unchanged into urine and that the active metabolites metabolite of levosimendan remain in the body longer than levosimendan. The remaining half of OR-1896 dose is eliminated through other metabolic routes, partially through interconversion back to OR-1855 with further metabolism of OR-1855. Given the fact that the pharmacological activity and potency of OR-1896 is similar to levosimendan, these results emphasize the clinical significance of OR-1896 and its contribution to the long-lasting effects of levosimendan.

Levosimendan and its metabolite OR-1896 elicit KATP channel-dependent dilation in resistance arteries in vivo

Pharmacol Rep 2013;65(5):1304-10.PMID:24399726DOI:10.1016/s1734-1140(13)71488-9.

Background: Levosimendan and its long-lived metabolite OR-1896 produce vasodilation in different types of vessels by activating ATP-sensitive (KATP) and other potassium channels. Methods: In the present study we applied intravital videomicroscopy to investigate the in situ effects of levosimendan and OR-1896 on the diameters of real resistance arterioles (rat cremaster muscle arterioles with diameters of ≈ 20 μm). Results: Levosimendan and OR-1896 induced concentration-dependent (1 nM - 100 μM) dilations to similar extents in these arterioles (maximal dilation from 23 ± 2 to 33 ± 2 μm and from 22 ± 1 to 32 ± 1 μm, respectively). The arteriolar dilations induced by the selective KATP channel opener pinacidil (1 nM - 10 μM) (maximal dilation from 22 ± 4 μm to 35 ± 3 μm) were diminished in the presence of the selective KATP channel blocker - glibenclamide (5 μM) (maximal diameter attained: 22 ± 1 μm). Glibenclamide also counteracted the maximal dilations in response to levosimendan or OR-1896 (to 23 ± 3 μm or 22 ± 5 μm, respectively). Conclusions: In conclusion, this is the first demonstration that levosimendan and OR-1896 elicit arteriolar dilation in vivo, via activation of KATP channels in real resistance vessels in the rat.