R-甲羟戊酸 | 17817-88-8

• 分子结构分类: 有机化合物 - 脂质和类脂质分子 - 脂肪酰基
• 中文名称: R-甲羟戊酸
• 英文名称: mevalonic acid
• 英文别名: mevalonate acid；mevalonate；(R)-3,5-dihydroxy-3-methyl-valeric acid；(R)-3,5-Dihydroxy-3-methyl-valeriansaeure；(R)-Mevalonsaeure；(3R)-3,5-dihydroxy-3-methylpentanoic acid
• CAS: 17817-88-8
• 化学式: C₆H₁₂O₄
• 分子量: 148.159
• InChiKey: KJTLQQUUPVSXIM-ZCFIWIBFSA-N

物化性质

• 沸点：
  364.1±32.0 °C(Predicted)
• 密度：
  1.263±0.06 g/cm3(Predicted)
• 溶解度：
  可溶于酸性水溶液（少许）、DMSO（少许）、水（少许）
• 物理描述：
  Solid
• 颜色/状态：
  Oily liquid
• 熔点：
  24-27°C
• 蒸汽压力：
  1.7X10-3 mm Hg at 25 °C (est)
• 解离常数：
  pKa = 4.24 (est)
• 碰撞截面：
  137.7 Ų [M+Na]+ [CCS Type: DT, Method: stepped-field]

计算性质

• 辛醇/水分配系数(LogP)：
  -1
• 重原子数：
  10
• 可旋转键数：
  4
• 环数：
  0.0
• sp3杂化的碳原子比例：
  0.83
• 拓扑面积：
  77.8
• 氢给体数：
  3
• 氢受体数：
  4

ADMET

毒理性

• 相互作用

研究了局部应用戊酸对小鼠表皮渗透屏障功能的影响，并将其与胆固醇进行了比较。使用丙酮进行局部治疗导致经表皮水分丢失呈线性增加，与治疗次数成比例，老年鼠的增加速度比年轻鼠更快。在老年鼠表皮上施用戊酸增强了其对损伤的抵抗力以及从急性屏障破坏中恢复屏障功能的速度。相比之下，尽管胆固醇也有同样的效果，但所需的量比戊酸高得多。在年轻鼠中，戊酸和胆固醇对抵抗丙酮损伤的能力以及对丙酮损伤恢复速度都没有影响。在局部施用戊酸的鼠皮肤中，观察到胆固醇合成和3-羟基-3-甲基戊二酸辅酶A还原酶活性的刺激，而等摩尔胆固醇的刺激则没有观察到。这些数据表明，局部应用戊酸增强了老年鼠的屏障恢复能力，这不仅伴随着从戊酸加速胆固醇合成，而且还刺激了整个胆固醇生物合成。

... The effect of topical mevalonic acid on the murine epidermal permeability barrier function /was investigated/, comparing it with that of cholesterol. Topical treatment with acetone caused linear increases in transepidermal water loss, in proportion to the number of treatments more rapidly in aged mice than in young mice. Administration of mevalonic acid on aged murine epidermis enhanced its resistance against damage and the recovery rate of barrier function from acute barrier disruption. In contrast, although cholesterol also had the same effect, it required a much higher amount than mevalonic acid. In young mice, neither mevalonic acid nor cholesterol had any effect on resistance against acetone damage nor the recovery rate from acetone damage. In the skin of mice topically administered with mevalonic acid, stimulation of cholesterol synthesis and 3-hydroxy-3-methylglutaryl coenzyme A reductase activity were both observed, whereas none was seen with stimulation by equimolar cholesterol. These data indicate that a topical application of mevalonic acid enhances barrier recovery in aged mice, which is accompanied by not only acceleration of cholesterol synthesis from mevalonic acid but also stimulation of the whole cholesterol biosynthesis.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

两种含有等量酒精（48克）的不同酒精饮料（一种是含有异戊二烯酸（啤酒），另一种不含有（伏特加））对7名健康受试者尿液中异戊二烯酸排泄和血清中异戊二烯酸浓度的影响进行了研究。晚上饮用含有608微克/升异戊二烯酸的1升啤酒，将使随后12小时尿液中异戊二烯酸的排泄量平均增加一倍以上，从103 ± 15微克/12小时增加到211 ± 17微克/12小时（P < 0.001；占给药剂量的18%）。饮用相同量的酒精作为伏特加没有影响，但在摄入两种酒精饮料后的第二天（早上7点到晚上7点），尿液中异戊二烯酸的排泄量略有增加。在摄入啤酒（从3.22 ± 0.20纳克/毫升增加到6.79 ± 0.58纳克/毫升）或伏特加（从3.23 ± 0.37纳克/毫升增加到5.36 ± 0.55纳克/毫升）后，第二天早晨血清中异戊二烯酸的浓度显著增加（P < 0.002）。血清中豆甾醇与胆固醇的比率也有所增加（分别增加了18%和25%），这是肝脏中3-羟基-3-甲基戊二酸辅酶A还原酶活性的另一个指标......使用异戊二烯酸作为胆固醇合成标志物的研究必须仔细监测饮食中异戊二烯酸的摄入量和酒精消费。

The influence of 2 different alcoholic beverages containing an equal amount of alcohol (48 g), 1 with mevalonic acid (beer) and 1 without (vodka), on the urinary excretion and serum concentration of mevalonic acid was investigated in 7 healthy subjects. Drinking 1 L of beer at night containing 608 ug/L mevalonic acid more than doubled the urinary excretion of mevalonic acid the following 12 hours, on average from 103 +/- 15 microg/12 h to 211 +/- 17 ug/12 hr (P < .001; 18% of the administered dose). Drinking the same amount of alcohol as vodka had no effect, but urinary mevalonic acid output increased slightly the following day (7 AM to 7 PM) after ingestion of both alcoholic beverages. Serum concentrations of mevalonic acid were significantly increased the following morning after ingestion of beer (from 3.22 +/- 0.20 ng/mL to 6.79 +/- 0.58 ng/mL) or vodka (from 3.23 +/- 0.37 ng/mL to 5.36 +/- 0.55 ng/mL, P < .002 for both). An increase in the ratio of lathosterol to cholesterol in serum, another indicator of 3beta-hydroxy-3beta-methylglutaryl coenzyme A reductase activity in the liver, was also observed (+18% and +25%, respectively). ... Studies using mevalonic acid as a marker of cholesterol synthesis must be carefully monitored regarding dietary mevalonic acid intake and alcohol consumption.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

戊二酸是HMG-CoA还原酶的产物，该酶对胆固醇生物合成至关重要。氟伐他汀（山德士化合物XU 62-320）是该酶的强效抑制剂，因此也抑制了戊二酸的产生。在三项独立的研究中，从妊娠第15天开始至断奶期间，给予交配的大鼠口服氟伐他汀12和24毫克/千克/天，结果在分娩时和哺乳期间出现了意想不到的母体死亡。在两项研究中进行显微镜评估，发现在濒死动物中有显著的心肌病。在一个或两个剂量水平上也观察到了与药物相关的临床体征、显著的母体体重下降以及死胎和新生儿死亡率的增加。在氟伐他汀给药的同时补充500毫克/千克，每天两次的戊二酸，完全阻止和/或改善了死亡、心肌病和其他不良影响。这些研究表明，在分娩前后观察到的氟伐他汀对母体的不良影响是由于在所给药量水平上过度发挥了药理活性，即抑制了HMG-CoA还原酶、其直接产物戊二酸以及胆固醇的生物合成。

Mevalonic acid is a product of the enzyme HMG-CoA reductase which is essential for cholesterol biosynthesis. Fluvastatin (Sandoz compound XU 62-320) is a potent inhibitor of this enzyme and, hence, mevalonic acid production. In three separate studies, oral administration of fluvastatin at 12 and 24 mg/kg/day to mated rats from day 15 of gestation through weaning resulted in unanticipated maternal mortality at the time of parturition and during lactation. Microscopic evaluations performed in two studies revealed significant cardiac myopathy in the dying animals. Drug-related clinical signs, significant maternal body weight loss, and an increase in stillborn pups and neonatal mortality were also noted at one or both dose levels. Supplementation of fluvastatin administration with 500 mg/kg b.i.d. of mevalonic acid completely blocked and/or ameliorated the mortality, cardiac myopathy, and other adverse effects. These studies indicate that the adverse maternal effects observed with fluvastatin before or following parturition resulted from exaggerated pharmacologic activity at the dose levels administered, i.e., inhibition of the enzyme HMG-CoA reductase, its immediate product mevalonic acid, and cholesterol biosynthesis.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

... 甲瓦龙酸阻止了阿托伐他汀对细胞因子刺激的血管细胞粘附分子-1表达及随后THP-1单核细胞对培养的内皮细胞的粘附的抑制作用。

... Mevalonic acid prevented the inhibitory effect of atorvastatin on cytokine-stimulated vascular cell adhesion molecule-1 expression and subsequent adhesion of THP-1 monocytes to the cultured endothelial cells.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 解毒与急救

/SRP:/ 立即急救：确保已经进行了充分的中毒物清除。如果患者停止呼吸，开始人工呼吸，最好使用需求阀复苏器、袋阀面罩装置或口袋面罩，按训练操作。如有必要，执行心肺复苏。立即用缓慢流动的水冲洗受污染的眼睛。不要催吐。如果发生呕吐，让患者前倾或置于左侧（如果可能的话，头部向下）以保持呼吸道畅通，防止吸入。保持患者安静，维持正常体温。寻求医疗帮助。 /毒物A和B/

/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

在夜间口服[13C2]戊糖酸后，约20% +/- 0.7%的剂量在随后的12小时内通过尿液排出，此后仅有微量排出。在第二天早晨未能检测到血清中的[13C2]戊糖酸。我们得出结论，膳食中戊糖酸的吸收以及酒精诱导的戊糖酸合成会影响这一胆固醇前体的尿排泄和血清浓度。

After oral administration of [13C2] mevalonic acid at night, 20% +/- 0.7% of the dose was excreted in urine the following 12 hours, and only trace amounts thereafter. No [13C2] mevalonic acid could be detected in serum the following morning. We conclude that the absorption of dietary mevalonic acid and alcohol-induced mevalonic acid synthesis affects the urinary excretion and serum concentration of this cholesterol precursor.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

尿液中介酸排泄作为胆固醇合成指标的研究。在正常血脂的志愿者中，介酸的排泄平均为3.51 ± 0.59 (SD) 微克/千克·天1；(n = 24) 并且与高胆固醇血症患者没有差异(3.30 ± 0.92 微克/千克·天1；n = 24)。在患有脑黄瘤病的患者中，排泄显著较高(8.55 ± 1.92 微克/千克·天1；n = 6, P < 0.001)，但与服用胆酸胺的志愿者相当(6.69 ± 2.6 微克/千克·天1；n = 5)。介酸24小时排泄与胆固醇合成之间存在显著相关性(r = 0.835；n = 35；P < 0.001)。连续3天排泄介酸的变化系数较小(9.8%；n = 7)。然而，介酸的夜间尿液排出量显著高于白天(164 ± 14 微克/12小时 vs 129 ± 9 微克/12小时；n = 11；P < 0.05)。在接受辛伐他汀(40毫克/天)治疗6周的患者中，早晨尿样中介酸与肌酐的比值与治疗前相比显著降低(110 ± 25 微克/克 vs 66 ± 25 微克/克；P < 0.001)。此外，早晨尿样中介酸与肌酐的比值与24小时收集期的比值相关(r = 0.714；n = 34；P < 0.001)。结果表明，无论是24小时收集还是单个早晨样本，尿液中介酸的分析是一种有吸引力的方法，用于评估胆固醇合成速率的长期和非常短期变化。

Urinary excretion of mevalonic acid was investigated as an indicator of cholesterol synthesis. In normolipemic volunteers, excretion of mevalonic acid averaged 3.51 +/- 0.59 (SD) ug/kg x day1; (n = 24) and was not different from patients with hypercholesterolemia (3.30 +/- 0.92 ug/kg x day1; n = 24). In patients with cerebrotendineous xanthomatosis, the excretion was significantly higher (8.55 +/- 1.92 ug/kg x day1; n = 6, P < 0.001) but comparable to volunteers treated with cholestyramine (6.69 +/- 2.6 ug/kg x day1; n = 5). A significant correlation was found between 24-hr excretion of mevalonic acid and cholesterol synthesis (r = 0.835; n = 35; P < 0.001). The coefficient of variation of excretion of mevalonic acid during 3 consecutive days was small (9.8%; n = 7). However, urinary output of mevalonic acid was significantly higher during the night (164 +/- 14 ug/12 hr) than during the day (129 +/- 9 ug/12 hr; n = 11; P < 0.05). In patients treated with simvastatin (40 mg/day) for 6 weeks, the ratio of mevalonic acid to creatinine in a morning urine sample decreased significantly compared to pretreatment values (110 +/- 25 ug/g vs. 66 +/- 25 ug/g; P < 0.001). Furthermore, the ratio of mevalonic acid to creatinine in a morning urine sample correlated with the ratio from the 24-hr collection period (r = 0.714; n = 34; P < 0.001). The results indicate that the analysis of urinary mevalonic acid, either in 24-hr collection or in a single morning sample, is an attractive method for evaluation of long and very short term changes of the rates of cholesterol synthesis.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

血浆异戊酸（MVA）浓度与（i）接受胆树脂治疗的患者的全身体胆固醇合成率增加（通过sterol-balance方法测量）相关，与（ii）接受高胆固醇饮食4周后的门诊患者全身体固醇合成率降低（通过新鲜分离的单核白细胞中标记醋酸转化为固醇来指示）相关。此外，在严格控制的代谢病房中，患者的血浆MVA浓度显示出昼夜节律。在节律的峰值（午夜到凌晨3点之间）MVA浓度比最低点（上午9点到中午之间）高3-5倍。进一步地，血浆MVA的昼夜节律与内源性胆固醇合成之间的关系得到了以下发现的暗示：血浆MVA节律被胆固醇喂食（每天1,200毫克）所抑制，并且在12天的禁食后消失...

... Plasma mevalonic acid (MVA) concentrations were correlated (i) with increased rates of whole-body cholesterol synthesis (measured by sterol-balance methods) in patients treated with cholestryamine resin (ii) with decreased rates of whole-body sterol synthesis (indicated by conversion of labeled acetate to sterol in freshly isolated mononuclear leukocytes) in out-patients after 4 weeks on a cholesterol-rich diet. In addition, a diurnal rhythm of plasma MVA concentrations was observed in patients whose activities were strictly controlled on a metabolic ward. At the peak of the rhythm (between midnight and 3 a.m.) MVA concentrations were 3-5 times greater than at the nadir (between 9 a.m. and noon). Furthermore, a relationship between the diurnal rhythm of plasma MVA and endogenous cholesterol synthesis is suggested by /the/ finding that the plasma MVA rhythm was suppressed by cholesterol feeding (1,200 mg/day) and abolished by a 12-day fast...

来源:Hazardous Substances Data Bank (HSDB)

反应信息

• 作为反应物：
  描述：

  R-甲羟戊酸 在 mevalonate kinase 、 isopentenyl kinase 、 mevalonate 5-phosphate dehydratase 、 trans-anhydromevalonate 5-phosphate decarboxylase 、 5’-三磷酸腺苷 作用下， 生成 isopentenyl pyrophosphate
  参考文献：
  名称：

  甲羟戊酸5-磷酸脱羧酶的底物特异性和工程化。

  摘要：

  最近在叶绿屈挠菌的细菌中发现了甲羟戊酸（MVA）途径的分支。在用于生物合成异戊烯基焦磷酸酯（IPP）的另一种方法中，倒数第二个步骤是将（R）-甲羟戊酸酯5-磷酸酯（（R）-MVAP）脱羧为异戊烯基磷酸酯（IP），然后进行ATP依赖异戊烯基磷酸激酶（IPK）催化IP磷酸化为IPP。值得注意的是，脱羧反应是由甲羟戊酸5-磷酸脱羧酶（MPD）催化的，该酶与经典MVA途径的甲羟戊酸二磷酸脱羧酶（MDD）具有相当的序列相似性。我们表明，最初被注释为嗜热变形挠单胞菌嗜热厌氧弯曲杆菌MDD的酶具有相同的（R）-MVAP和（R）-甲羟戊酸5-二磷酸酯（（R）-MVAPP）的催化效率。进一步，通过与（R）-MVAP或（R）-MVAPP结合的嗜热链球菌MPD / MDD的接近原子分辨率的X射线晶体结构，揭示了这种双重特异性的分子基础。这些发现与该细菌酶，功能性MDD和几种推定的MPD的序列和结构比较相结合，勾

  DOI：

  10.1021/acschembio.9b00322
• 作为产物：
  描述：

  甲瓦龙酸内酯 在 potassium hydroxide 作用下， 以 水 为溶剂， 反应 0.5h， 生成 R-甲羟戊酸
  参考文献：
  名称：

  定向进化导致的热稳定转酮酶的供体混杂：1-脱氧-d-木酮糖-5-磷酸合酶活性的有效补充

  摘要：

  催化不对称碳连接反应的酶通常对其亲核供体底物组分显示很高的底物特异性。通过定向体外进化对源自嗜热脂肪热地芽孢杆菌的热稳定的转酮醇酶进行结构导向的工程改造，产生了新的酶变体，该变体能够利用丙酮酸和更高的脂肪族同源物作为亲核组分进行酰基转移，而不是天然的多羟基化酮糖磷酸酯或羟基丙酮酸。单个突变体H102T证明对3-甲基-2-氧代丁酸酯作为供体的打击最大，而双突变体H102L / H474S对丙酮酸作为供体则显示出最高的催化效率。后一种变体能够补充大肠杆菌的营养缺陷型dxs基因缺失产生的细胞，该基因编码进入萜类生物合成的第一个重要步骤的活性，从而提供了机会进行生长选择测试以进一步优化酶。

  DOI：

  10.1002/anie.201701169

文献信息

• [EN] BENZAMIDE OR BENZAMINE COMPOUNDS USEFUL AS ANTICANCER AGENTS FOR THE TREATMENT OF HUMAN CANCERS<br/>[FR] COMPOSÉS BENZAMIDE OU BENZAMINE À UTILISER EN TANT QU'ANTICANCÉREUX POUR LE TRAITEMENT DE CANCERS HUMAINS
  申请人：UNIV TEXAS

  公开号：WO2017007634A1

  公开（公告）日：2017-01-12

  The described invention provides small molecule anti-cancer compounds for treating tumors that respond to cholesterol biosynthesis inhibition. The compounds selectively inhibit the cholesterol biosynthetic pathway in tumor-derived cancer cells, but do not affect normally dividing cells.

  所描述的发明提供了用于治疗对胆固醇生物合成抑制作出反应的肿瘤的小分子抗癌化合物。这些化合物选择性地抑制肿瘤来源的癌细胞中的胆固醇生物合成途径，但不影响正常分裂的细胞。
• [EN] MTP INHIBITING ARYL PIPERIDINES OR PIPERAZINES SUBSTITUTED WITH 5-MEMBERED HETEROCYCLES<br/>[FR] PIPERIDINES D'ARYLE OU PIPERAZINES SUBSTITUEES PAR DES HETEROCYCLES A 5 RAMIFICATIONS INHIBANT LA MTP
  申请人：JANSSEN PHARMACEUTICA NV

  公开号：WO2005085226A1

  公开（公告）日：2005-09-15

  The present invention is concerned with novel aryl piperidine or piperazine compounds substituted with certain 5-membered heterocycles having apoB secretion/MTP inhibiting activity and concomitant lipid lowering activity. The invention further relates to methods for preparing such compounds, pharmaceutical compositions comprising said compounds as well as the use of said compounds as a medicine for the treatment of hyperlipidemia, obesity and type II diabetes (Formula (I)). The invention further relates to methods for preparing such compounds, pharmaceutical compositions comprising said compounds as well as the use of said compounds as a medicine for the treatment of atherosclerosis, pancreatitis, obesity, hyper­triglyceridemia, hypercholesterolemia, hyperlipidemia, diabetes and type II diabetes.

  本发明涉及新颖的芳基哌啶或哌嗪化合物，其被某些含有apoB分泌/MTP抑制活性和伴随的降脂活性的5-成员杂环取代。该发明还涉及制备这种化合物的方法，包括所述化合物的药物组合物以及将所述化合物用作治疗高脂血症、肥胖症和2型糖尿病的药物的用途（公式（I））。该发明还涉及制备这种化合物的方法，包括所述化合物的药物组合物以及将所述化合物用作治疗动脉粥样硬化、胰腺炎、肥胖症、高甘油三酯血症、高胆固醇血症、高脂血症、糖尿病和2型糖尿病的药物的用途。
• Triamide-substituted heterobicyclic compounds
  申请人：Pfizer Inc.

  公开号：US20030187053A1

  公开（公告）日：2003-10-02

  The invention relates to triamide MTP/ApoB inhibitors of the formula 1 1 wherein R 1 -R 8 are as defined in the specification, as well as pharmaceutical compositions and uses thereof, and processes for preparing the compounds. The compounds of the invention are useful for the treatment of obesity and lipid disorders.

  本发明涉及三酰胺MTP/ApoB抑制剂，其化学公式为1，其中R1-R8如说明书所述，以及包含这些化合物的药物组合物及其用途，以及制备这些化合物的方法。本发明的化合物可用于治疗肥胖和脂质紊乱。
• Polyarylcarboxamides useful as lipid lowering agents
  申请人：——

  公开号：US20040014971A1

  公开（公告）日：2004-01-22

  Polyarylcarboxamide compounds of formula (I) 1 are useful as lipid lowering agents.

  多芳基羧酰胺化合物公式(I) 1 有助于降低血脂。
• Microsomal triglyceride transfer protein inhibitor
  申请人：Pfizer Inc

  公开号：US20040132745A1

  公开（公告）日：2004-07-08

  The present invention provides inhibitors of microsomal triglyceride transfer protein (MTP) and/or apolipoprotein B (Apo B) secretion having Formula (I) which are useful for the treatment of obesity and related diseases, as well as prevention and treatment of atherosclerosis and its clinical sequelae, for lowering serum lipids, and in the prevention and treatment of related diseases. The invention further relates to pharmaceutical compositions comprising the compounds of the present invention and to methods of treating obesity, atherosclerosis, and related diseases and/or conditions with the compounds of the present invention, either alone or in combination with other medicaments, including lipid-lowering agents. 1

  本发明提供了具有公式(I)的微粒体甘油三酯转运蛋白（MTP）和/或载脂蛋白B（Apo B）分泌抑制剂，用于治疗肥胖及相关疾病，以及预防和治疗动脉粥样硬化和其临床后遗症，降低血清脂质，以及预防和治疗相关疾病。本发明还涉及包含本发明化合物的药物组合物，以及使用本发明化合物单独或与其他药物（包括降脂药）联合治疗肥胖、动脉粥样硬化和相关疾病/状况的方法。