Bimoclomol
(Synonyms: 氯吡哌醇) 目录号 : GC32620
Bimoclomol是一种heatshockprotein(HSP)辅诱导剂，可用于心血管疾病的研究。
Cas No.:130493-03-7
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
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- Purity: >99.00%
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Cell experiment: | Using the same cell preparation, a cytoprotection (cell survival) assay is configured to assess the ability of bimoclomol to protect cells exposed to a lethal stress. To optimize the cell survival determinations, final plating densities for this protocol are reduced to approximately 0.5 million cells/mL. Plated cardiomyocytes are placed in an incubator (37°C, 5% CO2) for 24 h. The plates are removed from the incubator and the media changed to serum free. Separate sets of cells are either heat shocked at 42°C for 1 h or treated as sham (no heat shock). Bimoclomol is then added to individual wells at 0, 0.01, 0.1, 1, 10 and 100 μM and the plates are placed back in the 37°C incubator for 24 h. The plates are removed from the incubator and after another media change, (serum free) all plates are exposed to a lethal heat stress for 2 h in a waterbath set at 47°C. The plates are then placed back in the 37°C incubator overnight (16-18 h). The following morning, cell survival is determined using trypan blue exclusion. Equal volumes of culture medium and trypan blue solution are mixed. After removing the spent media from the wells, the above mixture is added to the wells for 10 min. The cells are then washed three times with cold PBS and counted with an inverted light microscope (10×). The final survival values from this protocol are expressed as the percentage of viable cells per treatment using the formula [(stained cells−total cells)÷total cells]×100. |
References: [1]. Jednakovits A, et al. In vivo and in vitro acute cardiovascular effects of bimoclomol. Gen Pharmacol. 2000 May;34(5):363-9. | |
Bimoclomol is a heat shock protein (HSP) coinducer, used for treatment of cardiovascular diseases.
Bimoclomol (40 μM) significantly increases coronary flow (CF) in the period of normoxic perfusion (before ischemia). Bimoclomol significantly increases LVDP and CO, but it decreases LVEDP under ischemic conditions. Bimoclomol displays a biphasic effect on the rate of relaxation. Bimoclomol (>10 μM) causes concentration-dependent vasorelaxation, with EC50 value of 214 μM. Bimoclomol (100 μM) induces vasorelaxation also against 20 mM KCl. However, bimoclomol fails to relax preparations precontracted with serotonin, PGF2 or angiotensin II[1]. Bimoclomol does not affect the stability of Hsp70 or its mRNA. Bimoclomol coinduces Hsp expression via the prolonged activation of the heat shock transcription factor (HSF-1). The effects of bimoclomol are abolished in cells from mice lacking HSF-1. Furthermore, bimoclomol can bind to HSF-1 and induce a prolonged binding of HSF-1 to the respective DNA elements[2]. Bimoclomol (0.1, 1 and 10 μM) improves cell survival of rat neonatal cardiomyocytes compared to vehicle-treated cells. Bimoclomol (0.01 to 10 μM) significantly elevates HSP70 levels, based on the time of exposure. Pretreatment with bimoclomol for 24 h significantly increases survival of cells[3].
Bimoclomol (1 and 5 mg/kg) decreases the ST-segment elevation induced by coronary occlusion by 56% and 80%, respectively, in anesthetized dogs[1].
[1]. Jednakovits A, et al. In vivo and in vitro acute cardiovascular effects of bimoclomol. Gen Pharmacol. 2000 May;34(5):363-9. [2]. Hargitai J, et al. Bimoclomol, a heat shock protein co-inducer, acts by the prolonged activation of heat shock factor-1. Biochem Biophys Res Commun. 2003 Aug 1;307(3):689-95. [3]. Polakowski JS, et al. Bimoclomol elevates heat shock protein 70 and cytoprotects rat neonatal cardiomyocytes. Eur J Pharmacol. 2002 Jan 18;435(1):73-7.
| Cas No. | 130493-03-7 | SDF | |
| 别名 | 氯吡哌醇 | ||
| Canonical SMILES | Cl/C(C1=CC=CN=C1)=N\OCC(O)CN2CCCCC2 | ||
| 分子式 | C14H20ClN3O2 | 分子量 | 297.78 |
| 溶解度 | DMSO : 100 mg/mL (335.82 mM; Need ultrasonic) | 储存条件 | Store at -20°C |
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| 1 mM | 3.3582 mL | 16.7909 mL | 33.5818 mL |
| 5 mM | 0.6716 mL | 3.3582 mL | 6.7164 mL |
| 10 mM | 0.3358 mL | 1.6791 mL | 3.3582 mL |
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Multilateral in vivo and in vitro protective effects of the novel heat shock protein coinducer, Bimoclomol: results of preclinical studies
Cardiovasc Drug Rev 2001 Summer;19(2):133-51.PMID:11484067DOI:10.1111/j.1527-3466.2001.tb00060.x.
Bimoclomol, the recently developed non-toxic heat shock protein (HSP) coinducer, was shown to display multilateral protective activities against various forms of stress or injuries at the level of the cell, tissue or organism. The compound enhanced the transcription, translation and expression of the 70 kD heat shock protein (HSP-70) in myogenic and HeLa cell lines exposed to heat stress, and increased cell survival on exposure to otherwise lethal thermal injury. Bimoclomol increased contractility of the working mammalian heart, this effect was associated with the increased intracellular calcium transients due to increased probability of opening of ryanodine receptors in the sarcoplasmic reticulum (SR). In healthy tissues these cardiac effects were evident only at relatively high concentrations of the drug, while in the ischemic myocardium Bimoclomol exerted significant cardioprotective and antiarrhythmic effects at submicromolar concentrations. It decreased ischemia-induced reduction of contractility and of cardiac output, and dramatically decreased the elevation of the ST-segment during ischemia as well as the occurrence of ventricular fibrillation upon reperfusion. Bimoclomol was also active in various pathological animal models subjected to acute or chronic stress. In the spontaneously hypertensive rats chronic pretreatment with Bimoclomol restored sensitivity of aortic rings to acetylcholine; this effect was accompanied by accumulation of HSP-70 in the tissues. Bimoclomol pretreatment significantly diminished the consequences of vascular disorders associated with diabetes mellitus. Diabetic neuropathy, retinopathy, and nephropathy were prevented or diminished, while wound healing was enhanced by Bimoclomol. Enhancement of wound healing by Bimoclomol was observed after thermal injury as well as following ultraviolet (UV) irradiation. In addition to the beneficial effects on peripheral angiopathies, Bimoclomol antagonized the increase in permeability of blood-brain barrier induced by subarachnoid hemorrhager or arachidonic acid. A general and very important feature of the above effects of Bimoclomol was that the drug failed to cause alterations under physiological conditions (except the enhanced calcium release from cardiac sarcoplasmic reticulum). Bimoclomol was effective only under conditions of stress. Consistent with its HSP-coinducer property, Bimoclomol alone had very little effect on HSP production. Its protective activity became apparent only in the presence of cell damage. Currently, Bimoclomol reached the end of the Phase II clinical trial in a group of 410 patients with diabetic complications. Results of this trial will answer the question, whether a compound with promising in vitro and in vivo preclinical findings will produce the anticipated beneficial effects in humans. In the event of a positive outcome of this trial, the indications for Bimoclomol will be substantially extended.
Bimoclomol, a heat shock protein co-inducer, acts by the prolonged activation of heat shock factor-1
Biochem Biophys Res Commun 2003 Aug 1;307(3):689-95.PMID:12893279DOI:10.1016/s0006-291x(03)01254-3.
The novel hydroxylamine derivative, Bimoclomol, has been shown previously to act as a co-inducer of several heat shock proteins (Hsp-s), enhancing the amount of these proteins produced following a heat shock compared to heat shock alone. Here we show that the co-inducing effect of Bimoclomol on Hsp expression is mediated via the prolonged activation of the heat shock transcription factor (HSF-1). Bimoclomol effects are abolished in cells from mice lacking HSF-1. Moreover, Bimoclomol binds to HSF-1 and induces a prolonged binding of HSF-1 to the respective DNA elements. Since HSF-1 does not bind to DNA in the absence of stress, the bimoclomol-induced extension of HSF-1/DNA interaction may contribute to the chaperone co-induction of Bimoclomol observed previously. These findings indicate that Bimoclomol may be of value in targeting HSF-1 so as to induce up-regulation of protective Hsp-s in a non-stressful manner and for therapeutic benefit.
Bimoclomol elevates heat shock protein 70 and cytoprotects rat neonatal cardiomyocytes
Eur J Pharmacol 2002 Jan 18;435(1):73-7.PMID:11790380DOI:10.1016/s0014-2999(01)01551-5.
Bimoclomol is a new compound that improves cell survival under experimental stress conditions partly by increasing intracellular heat shock proteins (HSPs). HSPs, especially HSP70, play a cytoprotective role in the rat heart. Rat neonatal cardiomyocytes were used to determine the ability of Bimoclomol to induce HSP70 and affect cell survival across a broad concentration range (0.01-100 microM). Bimoclomol significantly elevated HSP70 levels at concentrations ranging from 0.01 to 10 microM, depending on the time of exposure. Pretreatment with Bimoclomol for 24 h significantly increased survival of cells. There was a significant correlation between the increased levels of HSP70 and the increase in cell survival as a result of the treatment with Bimoclomol. In conclusion, Bimoclomol improved cell survival in rat neonatal cardiomyocytes, in part, by increasing the levels of HSP70. This cytoprotection began at the relatively low concentration of 0.1 microM, which is a concentration that can be achieved clinically.
Oral Bimoclomol elevates heat shock protein 70 and reduces myocardial infarct size in rats
Eur J Pharmacol 2002 Jan 18;435(1):79-83.PMID:11790381DOI:10.1016/s0014-2999(01)01552-7.
Bimoclomol has been shown to increase an inducible member of the heat shock protein 70 family (HSP70) and cytoprotect in vitro. Here, we addressed whether oral pretreatment of rats with Bimoclomol could elevate myocardial HSP70 and reduce infarct size in a rat model of ischemia and reperfusion. Rats were pretreated with Bimoclomol at 3, 6 or 18 h or with 42 degrees thermal stress 24 h before ischemia. Infarct size was significantly decreased 6 h after oral administration of Bimoclomol and 24 h after thermal stress. Left ventricles from a separate group of rats were examined for HSP70 levels. Western blots showed a significant increase in HSP70 6 h after oral administration of Bimoclomol and 24 h after thermal stress. There was a significant correlation (P<0.05) between HSP70 induction and infarct size reduction, whether produced by thermal stress or oral administration of Bimoclomol. Thus, Bimoclomol can increase HSP70 and reduce infarct size in a rat model of ischemia and reperfusion.
Bimoclomol protects against vascular consequences of experimental subarachnoid hemorrhage in rats
Brain Res Bull 1998;45(2):163-6.PMID:9443834DOI:10.1016/s0361-9230(97)00333-x.
Bimoclomol (BRLP-42) is a novel antiischemic compound acting against peripheral vascular complications of diabetes mellitus (neuropathy, retinopathy, and nephropathy). In the present study the activity of Bimoclomol was tested in experimental subarachnoid hemorrhage (SAH) and arachidonic acid (AA)-induced brain edema in rats to elucidate whether the compound may also have beneficial effect in cerebrovascular disturbances. For comparison, a neuroprotective AMPA antagonist, GYKI-52466, was examined. Injury caused by autologous intracranial blood injection or sodium-arachidonate was evaluated by the damage of blood-brain barrier (BBB) reflected in the extravasation of Evans blue dye into the cerebral tissue. Bimoclomol (2 x 2 mg/kg IV) markedly reduced, while GYKI-52466 (2 x 2 mg/kg IV) moderately diminished the extravasation produced by SAH (39.9%, p < 0.01 and 26.7%, p > 0.05, respectively). In the case of AA-induced brain edema, Bimoclomol showed less pronounced (19.6%, p < 0.05) inhibitory action, and GYKI-52466 seemed to be more effective (34.2%, p < 0.05). These results suggest that Bimoclomol may be active not only in peripheral micro- and macroangiopathy, but also in some types of cerebrovascular disorders.