Lapaquistat acetate
(Synonyms: TAK-475) 目录号 : GC38807
Lapaquistat acetate (TAK-475) 是一种角鲨烯合酶 (squalene synthase) 抑制剂，可阻止法呢基二磷酸酯 (FPP) 转化为角鲨烯。Lapaquistat acetate (TAK-475) 最初旨在用于甲羟戊酸激酶缺乏症 (MKD)，可有效降低低密度脂蛋白胆固醇，但可能引起肝脏损害。
Cas No.:189060-13-7
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Lapaquistat acetate (TAK-475) is a squalene synthase inhibitor, blocking the conversion of farnesyl diphosphate (FPP) to squalene[1]. Lapaquistat acetate (TAK-475) is originally intended use to Mevalonate Kinase Deficiency (MKD), it is effective at lowering low-density lipoprotein cholesterol, but it might cause liver damage[2].
[1]. Stein EA, et al. Lapaquistat acetate: development of a squalene synthase inhibitor for the treatment of hypercholesterolemia. Circulation. 2011 May 10;123(18):1974-85. [2]. Marcuzzi A, et al. Repositioning of Tak-475 In Mevalonate Kinase Disease: Translating Theory Into Practice. Curr Med Chem. 2018;25(24):2783-2796.
| Cas No. | 189060-13-7 | SDF | |
| 别名 | TAK-475 | ||
| Canonical SMILES | O=C(O)CC1CCN(C(C[C@@H]2C(N(CC(C)(C)COC(C)=O)C3=CC=C(Cl)C=C3[C@@H](C4=CC=CC(OC)=C4OC)O2)=O)=O)CC1 | ||
| 分子式 | C33H41ClN2O9 | 分子量 | 645.14 |
| 溶解度 | DMSO: 46 mg/mL (71.30 mM) | 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 | 1.5501 mL | 7.7503 mL | 15.5005 mL |
| 5 mM | 0.31 mL | 1.5501 mL | 3.1001 mL |
| 10 mM | 0.155 mL | 0.775 mL | 1.5501 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 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 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
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。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
Lapaquistat acetate: development of a squalene synthase inhibitor for the treatment of hypercholesterolemia
Circulation 2011 May 10;123(18):1974-85.PMID:21518985DOI:10.1161/CIRCULATIONAHA.110.975284.
Background: Lapaquistat acetate is a squalene synthase inhibitor investigated for the treatment of hypercholesterolemia. Methods and results: This report summarizes the phase 2 and 3 results from the lapaquistat clinical program, which was halted at an advanced stage as a result of potential hepatic safety issues. Efficacy and safety data were pooled from 12 studies (n=6151). These were 6- to 96-week randomized, double-blind, parallel, placebo- or active-controlled trials with lapaquistat monotherapy or coadministration with other lipid-altering drugs in dyslipidemic patients, including a large (n=2121) 96-week safety study. All studies included lapaquistat 100 mg daily; 5 included 50 mg; and 1 included 25 mg. The main outcome measures were the percent change in low-density lipoprotein cholesterol, secondary lipid/metabolic parameters, and overall safety. Lapaquistat 100 mg significantly decreased low-density lipoprotein cholesterol by 21.6% in monotherapy and by 18.0% in combination with a statin. It also reduced other cardiovascular risk markers, such as C-reactive protein. Total adverse events were higher for lapaquistat than placebo, although individual events were generally similar. At 100 mg, there was an increase in alanine aminotransferase value ≥3 times the upper limit of normal on ≥2 consecutive visits (2.0% versus 0.3% for placebo in the pooled efficacy studies; 2.7% versus 0.7% for low-dose atorvastatin in the long-term study). Two patients receiving lapaquistat 100 mg met the Hy Law criteria of alanine aminotransferase elevation plus increased total bilirubin. Conclusions: Squalene synthase inhibition with Lapaquistat acetate, alone or in combination with statins, effectively lowered low-density lipoprotein cholesterol in a dose-dependent manner. Elevations in alanine aminotransferase, combined with a rare increase in bilirubin, presented potential hepatic safety issues, resulting in termination of development. The lapaquistat experience illustrates the current challenges in lipid-altering drug development. Clinical trial registration: URL: http://www.clinicaltrials.gov. Unique identifiers: NCT00487994, NCT00143663, NCT00143676, NCT00864643, NCT00263081, NCT00286481, NCT00249899, NCT00249912, NCT00813527, NCT00256178, NCT00268697, and NCT00251680.
Lapaquistat acetate, a squalene synthase inhibitor, changes macrophage/lipid-rich coronary plaques of hypercholesterolaemic rabbits into fibrous lesions
Br J Pharmacol 2008 Jul;154(5):949-57.PMID:18587443DOI:10.1038/bjp.2008.143.
Background and purpose: Inhibition of squalene synthesis could transform unstable, macrophage/lipid-rich coronary plaques into stable, fibromuscular plaques. We have here treated WHHLMI rabbits, a model for coronary atherosclerosis and myocardial infarction, with a novel squalene synthase inhibitor, Lapaquistat acetate (TAK-475). Experimental approach: Young male WHHLMI rabbits were fed a diet supplemented with Lapaquistat acetate (100 or 200 mg per kg body weight per day) for 32 weeks. Serum lipid levels were monitored every 4 weeks. After the treatment, lipoprotein lipid and coenzyme Q10 levels were assayed, and coronary atherosclerosis and xanthomas were examined histopathologically or immunohistochemically. From histopathological and immunohistochemical sections, the composition of the plaque was analysed quantitatively with computer-assisted image analysis. Xanthoma was evaluated grossly. Key results: Lapaquistat acetate decreased plasma cholesterol and triglyceride levels, by lowering lipoproteins containing apoB100. Development of atherosclerosis and xanthomatosis was suppressed. Accumulation of oxidized lipoproteins, macrophages and extracellular lipid was decreased in coronary plaques of treated animals. Treatment with Lapaquistat acetate increased collagen concentration and transformed coronary plaques into fibromuscular plaques. Lapaquistat acetate also suppressed the expression of matrix metalloproteinase-1 and plasminogen activator inhibitor-1 in the plaque and increased peripheral coenzyme Q10 levels. Increased coenzyme Q10 levels and decreased very low-density lipoprotein cholesterol levels were correlated with improvement of coronary plaque composition. Conclusion and implications: Inhibition of squalene synthase by Lapaquistat acetate delayed progression of coronary atherosclerosis and changed coronary atheromatous plaques from unstable, macrophage/lipid accumulation-rich, lesions to stable fibromuscular lesions.
Protective effects of a squalene synthase inhibitor, Lapaquistat acetate (TAK-475), on statin-induced myotoxicity in guinea pigs
Toxicol Appl Pharmacol 2007 Aug 15;223(1):39-45.PMID:17599378DOI:10.1016/j.taap.2007.05.005.
High-dose statin treatment has been recommended as a primary strategy for aggressive reduction of LDL cholesterol levels and protection against coronary artery disease. The effectiveness of high-dose statins may be limited by their potential for myotoxic side effects. There is currently little known about the molecular mechanisms of statin-induced myotoxicity. Previously we showed that T-91485, an active metabolite of the squalene synthase inhibitor Lapaquistat acetate (lapaquistat: a previous name is TAK-475), attenuated statin-induced cytotoxicity in human skeletal muscle cells [Nishimoto, T., Tozawa, R., Amano, Y., Wada, T., Imura, Y., Sugiyama, Y., 2003a. Comparing myotoxic effects of squalene synthase inhibitor, T-91485, and 3-hydroxy-3-methylglutaryl coenzyme A. Biochem. Pharmacol. 66, 2133-2139]. In the current study, we investigated the effects of lapaquistat administration on statin-induced myotoxicity in vivo. Guinea pigs were treated with either high-dose cerivastatin (1 mg/kg) or cerivastatin together with lapaquistat (30 mg/kg) for 14 days. Treatment with cerivastatin alone decreased plasma cholesterol levels by 45% and increased creatine kinase (CK) levels by more than 10-fold (a marker of myotoxicity). The plasma CK levels positively correlated with the severity of skeletal muscle lesions as assessed by histopathology. Co-administration of lapaquistat almost completely prevented the cerivastatin-induced myotoxicity. Administration of mevalonolactone (100 mg/kg b.i.d.) prevented the cerivastatin-induced myotoxicity, confirming that this effect is directly related to HMG-CoA reductase inhibition. These results strongly suggest that cerivastatin-induced myotoxicity is due to depletion of mevalonate derived isoprenoids. In addition, squalene synthase inhibition could potentially be used clinically to prevent statin-induced myopathy.
Repositioning of Tak-475 In Mevalonate Kinase Disease: Translating Theory Into Practice
Curr Med Chem 2018;25(24):2783-2796.PMID:28901277DOI:10.2174/0929867324666170911161417.
Background: Mevalonate Kinase Deficiency (MKD, OMIM #610377) is a rare autosomal recessive metabolic and inflammatory disease. In MKD, defective function of the enzyme mevalonate kinase, due to a mutation in the MVK gene, leads to the shortage of mevalonate- derived intermediates, which results in unbalanced prenylation of proteins and altered metabolism of sterols. These defects lead to a complex multisystem inflammatory and metabolic syndrome. Objective: Although biologic therapies aimed at blocking the inflammatory cytokine interleukin- 1 can significantly reduce inflammation, they cannot completely control the clinical symptoms that affect the nervous system. For this reason, MKD can still be considered an orphan drug disease. The availability of MKD models reproducing the MKD-systematic inflammation, is crucial to improve the knowledge on its pathogenesis, which is still unknown. New therapies are also required in order to improve pateints' conditions and their quality of life. Methods: MKD-cellular models can be obtained by biochemical inhibition of mevalonatederived isoprenoids. Of note, these cells present an exaggerated response to inflammatory stimuli that can be reduced by treatment with zaragozic acid, an inhibitor of squalene synthase, thus increasing the availability of isoprenoids intermediates upstream the enzymatic block. Results: A similar action might be obtained by Lapaquistat acetate (TAK-475, Takeda), a drug that underwent extensive clinical trials as a cholesterol lowering agent 10 years ago, with a good safety profile. Conclusions: Here we describe the preclinical evidence supporting the possible repositioning of TAK-475 from its originally intended use to the treatment of MKD and discuss its potential to modulate the mevalonate pathway in inflammatory diseases.
Gateways to clinical trials
Methods Find Exp Clin Pharmacol 2008 Apr;30(3):231-51.PMID:18597009doi
(-)-Epigallocatechin gallate, (-)-Gossypol; Ad.hIFN-beta, AF-37702, Agatolimod sodium, Agomelatine, Alvocidib hydrochloride, ARC-1779; Belimumab, BIBW-2992, Binodenoson, Bortezomib, Bosutinib, Brivaracetam; Cediranib, Clevidipine, CNTO-328, CP-751871, Curcumin; Darapladib, Deforolimus, Denosumab, Desvenlafaxine succinate, Dipyridamole/prednisolone, Dronedarone hydrochloride, DTPw-HBV/Hib 2.5; Ecogramostim, Elacytarabine, Eltrombopag, Eprodisate sodium; Farnesylthiosalicylic acid, Febuxostat, Fenretinide, Ferumoxytol, FMP2.1/AS02A, Forodesine hydrochloride, FP-0011; HuLuc-63, Human Fibroblast Growth Factor 1; Idraparinux sodium, Indium 111 (111In) ibritumomab tiuxetan, Interleukin-21, Ipilimumab, ISS-1018, ITF-2357; Lapaquistat acetate, Laropiprant, Liposomal vincristine, LY-518674; Masitinib mesylate, MAXY-G34, MGCD-0103, Midostaurin, Mitumprotimut-T, MK-0343, MLN-1202, MM-093, Motexafin gadolinium; NB-001, NB-002, Niacin/laropiprant; Oblimersen sodium, Ocrelizumab, Omacetaxine mepesuccinate; Panobinostat, Patupilone, PBI-1402, Perifosine, PHA-739358, Plerixafor hydrochloride, Prasugrel; Regadenoson, RHAMM R3 peptide, Rilonacept, Rivaroxaban, Romiplostim; Safinamide mesilate, Salinosporamide A, Selenite sodium, Sotrastaurin; Thrombin alfa, Tipifarnib, TRO-19622; Vatalanib succinate, Vernakalant hydrochloride, VRC-WNVDNA017-00-VP; YM-155, Yttrium 90 (90Y) ibritumomab tiuxetan; Zosuquidar trihydrochloride.