HMR 1556
目录号 : GC34616
HMR1556，色氨醇衍生物，是一种IKs阻滞剂，在犬和豚鼠的左心室肌细胞中的IC50值分别为10.5nM、34nM。
Cas No.:223749-46-0
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
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- Purity: >99.50%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
HMR 1556, a chromanol derivative, is a IKs blocker with IC50s of 10.5 nM and 34 nM in canine and guinea pig left ventricular myocytes, respectively[1][2]. IC50: 10.5 nM (IKs in canine left ventricular myocytes), 34 nM (IKs in guinea pig left ventricular myocytes)[1]
HMR 1556 inhibits Ito, ICa,L and IKr with IC50s of 33.9 μM, 27.5 μM, 12.6 μM in canine left ventricular myocytes, respectively[1].
[1]. Thomas GP, et al. HMR 1556, a potent and selective blocker of slowly activating delayed rectifier potassium current. J Cardiovasc Pharmacol. 2003 Jan;41(1):140-7. [2]. Gerlach U,et al. Synthesis and activity of novel and selective I(Ks)-channel blockers. J Med Chem. 2001 Nov 8;44(23):3831-7.
| Cas No. | 223749-46-0 | SDF | |
| Canonical SMILES | CS(N([C@H]1C2=CC(OCCCC(F)(F)F)=CC=C2OC(C)(C)[C@@H]1O)C)(=O)=O | ||
| 分子式 | C17H24F3NO5S | 分子量 | 411.44 |
| 溶解度 | Soluble in DMSO | 储存条件 | Store at -20°C |
| General tips | 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。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 2.4305 mL | 12.1524 mL | 24.3049 mL |
| 5 mM | 0.4861 mL | 2.4305 mL | 4.861 mL |
| 10 mM | 0.243 mL | 1.2152 mL | 2.4305 mL |
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| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
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| % DMSO % % Tween 80 % saline | ||||||||||
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工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
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HMR 1556, a potent and selective blocker of slowly activating delayed rectifier potassium current
J Cardiovasc Pharmacol 2003 Jan;41(1):140-7.PMID:12500032DOI:10.1097/00005344-200301000-00018.
The slowly activating delayed rectifier potassium current (IKs) contributes prominently to ventricular repolarization of the cardiac action potential. Development of a selective IKs blocker is important for the elucidation of the physiologic and pathophysiologic relevance of IKs and the development of antiarrhythmic strategies. HMR 1556 [(3R,4S)-(+)-N-[3-hydroxy-2,2-dimethyl-6-(4,4,4-trifluorobutoxy) chroman-4-yl]-N-methylmethanesulfonamide] is a new chromanol derivative developed as a selective IKs blocker. Chromanol 293B, the most specific IKs blocker currently available, also inhibits the transient outward current (Ito). HMR 1556 was examined for its effects on IKs compared with rapidly activating delayed rectifier (IKr), inward rectifier (IK1), Ito, and L-type calcium (ICa.L) currents in canine left ventricular myocytes. HMR 1556 (0.5-500 nM ) inhibited IKs in a concentration-dependent manner (IC50 of 10.5 nM, compared with chromanol 293B's IC50 of 1.8microM). Inhibition of Ito was observed only at relatively high concentrations (IC50 of 33.9 microM comparable to chromanol 293B's IC of 38 microM). High concentrations of HMR 1556 also inhibited ICa.L (IC of 27.5 microM) and IKr (IC50 of 12.6 microM) while IK1 was unaffected. Our results indicate that HMR 1556 is superior to chromanol 293B in its potency and specificity for inhibition of IKs, making it a valuable experimental tool and a potential therapeutic agent.
Effects of the chromanol HMR 1556 on potassium currents in atrial myocytes
Naunyn Schmiedebergs Arch Pharmacol 2003 Mar;367(3):281-8.PMID:12644901DOI:10.1007/s00210-002-0672-5.
Purpose: The chromanol HMR 1556 is a potent blocker of KvLQT1/minK potassium channels expressed in Xenopus oocytes. The compound is therefore a new class III antiarrhythmic drug with a distinct mechanism of action. However, the effect of HMR 1556 on atrial ion channels and the selectivity of block in the human heart has not been investigated. We tested the effects of HMR 1556 on repolarizing potassium currents in human and guinea pig atrial myocytes. Methods and results: Single atrial myocytes were isolated by enzymatic dissociation. Atrial potassium currents (I(Ks), I(Kr), in guinea pig, I(to), I(Kur), I(K1) in humans) were recorded at 36 degrees C in the whole cell mode of the patch clamp technique. HMR 1556 produced a concentration-dependent and reversible block of I(Ks) with a half maximal concentration (EC(50)) of 6.8 nmol/l. 10 micromol/l HMR 1556 almost completely inhibited I(Ks) (97.2+/-3.2%, n=6). Steady-state activation as well as kinetic properties of the current were not altered by HMR 1556. I(Kr) currents were not affected up to concentrations of 10 micromol/l. HMR 1556 did not inhibit other potassium currents in human atrium: I(to), I(Kur) and the classical inward rectifier potassium current I(K1) were not significantly affected up to concentrations that completely blocked I(Ks) (10 micromol/l). Conclusions: HMR 1556 is a highly-potent blocker of I(Ks) channels without exerting effects on other potassium currents involved in atrial repolarization. Given the potential advantages of I(Ks) vs. I(Kr) blockade, the drug's new mechanism of action warrants further investigation to clarify its role as an antiarrhythmic agent.
Inhibition of IKs channels by HMR 1556
Naunyn Schmiedebergs Arch Pharmacol 2000 Dec;362(6):480-8.PMID:11138839DOI:10.1007/s002100000284.
Chromanol HMR 1556 [(3R,4S)-(+)-N-[3-hydroxy-2,2-dimethyl-6-(4,4,4-trifluorobutoxy)chroman-4-yl]-N-methylmethanesulfonamide], a novel inhibitor of the slow component of the delayed outward current in heart muscle cells (IKs), has been characterized in several in-vitro systems. mRNA encoding for the human protein minK was injected into Xenopus oocytes, leading to the expression of IKs channels. HMR 1556 inhibited this current half-maximally at a concentration of 120 nmol/l (IC50). Expression of the K+ channels Herg, Kv 1.5, Kv 1.3 and Kir2.1, and also the cationic current HCN2, were blocked little or not at all by 10 micromol/l HMR 1556. In isolated ventricular myocytes from the guinea pig the whole-cell patch-clamp method revealed inhibition of the IKs current with an IC50, of 34 nmol/l. Other current components, like IKr and IK1. were only slightly blocked at an HMR 1556 concentration of 10 micromol/l, whereas 10 micromol/l HMR 1556 inhibited the transient outward current I(to) and the sustained outward current I(sus) in rat ventricular myocytes by 25% and 36%, respectively. The L-type Ca2+ channel in guinea pig cardiomyocytes was blocked by 10 micromol/l HMR 1556 by 31%. Guinea pig right papillary muscles were investigated by the micropuncture technique at various pacing rates. In the frequency range of 0.5-7 Hz HMR 1556 (1 micromol/l) caused a prolongation of the action potential duration at 90% repolarization (APD90) by 19%-27%. In the presence of isoproterenol (10 micromol/l) the prolongation of the APD90 was more pronounced at low pacing rates (47% at 0.5 Hz and 35% at 1 Hz, compared with 25% at 7 Hz). The monophasic action potential was recorded in Langendorff-perfused guinea pig hearts. In spontaneously beating preparations, HMR 1556, at 0.1 micromol/l and 1 micromol/l, prolonged the MAPD90 by 3% and 10%, respectively, with no further prolongation at 10 micromol/l. The prolongation was much greater at low pacing rates [25% at 100 beats per min (bpm) and 13% at 150 bpm] than at fast pacing rates (9% at 350 bpm). The left ventricular pressure LVPmax was not affected at 1 micromol/l HMR 1556, but it decreased by 15% at 10 micromol/l. Other parameters, like the heart rate and coronary flow, were only slightly decreased at 1 micromol/l HMR 1556. In conclusion, HMR 1556 is a potent and selective inhibitor of the IKs current in guinea pig ventricular myocytes. The prolongation of the action potential duration is maintained at fast pacing rates.
Blockade of IKs by HMR 1556 increases the reverse rate-dependence of refractoriness prolongation by dofetilide in isolated rabbit ventricles
Br J Pharmacol 2006 Jun;148(3):255-63.PMID:16565733DOI:10.1038/sj.bjp.0706721.
1. The rate-dependent contributions of the rapid and slow components of the cardiac delayed rectifier K+ current (IKr and IKs, respectively) to repolarization are not fully understood. It is unclear whether the addition of IKs block will attenuate reverse rate-dependence seen after IKr block. 2. The individual and combined electrophysiological effects of selective IKr and IKs blockers, dofetilide and HMR 1556, respectively, were evaluated using Langendorff-perfused rabbit hearts. Monophasic action potential duration at 90% repolarization (MAPD90) and ventricular effective refractory period (VERP) were determined at cycle lengths (CLs) of 200-500 ms (at 50 ms intervals). 3. Dofetilide (1-100 nM) prolonged MAPD90 in a concentration-dependent manner (P < 0.001, n = 6) with reverse rate-dependence (P < 0.0001). In contrast, HMR 1556 (10-240 nM) alone did not prolong MAPD90. However, in the presence of 7.5 nM dofetilide, HMR 1556 (100 nM) increased the extent of reverse rate-dependence by further prolonging MAPD90 at CLs of 400, 450 and 500 ms (P < 0.05, n = 9) and, to a lesser extent, at shorter CLs (e.g. by 17 +/- 4 ms at CL 500 vs 2 +/- 3 ms at CL 200 ms). 4. Effects of dofetilide and HMR 1556 on VERP were similar to those on MAPD90. The slope of the VERP vs CL relation was steeper after the combination (0.081 +/- 0.013) than after dofetilide alone (0.028 +/- 0.018, P < 0.01, n = 9). 5. Blockade of rabbit IKs increased reverse rate-dependence of IKr block.
The new selective I(Ks)-blocking agent HMR 1556 restores sinus rhythm and prevents heart failure in pigs with persistent atrial fibrillation
Basic Res Cardiol 2005 May;100(3):270-8.PMID:15795798DOI:10.1007/s00395-005-0522-y.
Background: Antiarrhythmic drugs for treatment of atrial fibrillation in patients with heart failure are limited by proarrhythmia and low efficacy. Experimental studies indicate that the pure I(Ks) blocking agents chromanol 293b and HMR 1556 prolong repolarization more markedly at fast than at slow heart rates and during beta-adrenergic stimulation. These properties may overcome some of the above quoted limitations. Methods and results: Ten domestic swine underwent pacemaker implantation (PM) and atrial burst pacing to induce persistent AF. Four days after onset of persistent AF, pigs were randomized to HMR 1556 (30 mg/kg, p.o., 10 days) or placebo. All animals receiving HMR 1556 converted to SR (5.2 +/- 1.9 days), whereas placebo pigs remained in AF. Pigs treated with placebo developed high ventricular rates (297 +/- 5 bpm) and severe heart failure, whereas pigs treated with HMR 1556 remained hemodynamically stable. Left ventricular ejection fraction on the day of euthanization was significantly lower in the placebo compared to the HMR 1556 group (30 +/- 4% vs. 69 +/- 5%, p < 0.005). Similar results were seen with epinephrine levels (placebo 1563 +/- 193 pmol/l vs. HMR 613 +/-196 pmol/l, p < 0.05). Right atrial monophasic action potentials were significantly longer in the HMR 1556 compared to the placebo group (230 +/- 7 ms vs. 174 +/- 13 ms, p < 0.05). Conclusions: The new I(Ks) blocker HMR 1556 efficiently and safely restores SR and prevents CHF in a model of persistent AF. Restoration of SR is most likely linked to a marked prolongation of atrial repolarization even at high heart rates.