骨化三醇 | 32222-06-3

• 物质功能分类: 原料药 - 维生素类与矿物质类药 - 维生素AD类药
• 分子结构分类: 有机化合物 - 脂质和类脂质分子 - 类固醇和类固醇衍生物
• 中文名称: 骨化三醇
• 中文别名: 1Α,25-羟胆钙化醇；钙三醇；1α,25-二羟基维生素D3；(5Z,7E)-(1S,3R)-9,10-开环胆甾-5,7,10(19)-三烯-1,3,25-三醇；二羟胆钙化醇；罗钙全；骨化3醇；1,25-羟维生素D3
• 英文名称: calcitriol
• 英文别名: 1α,25-dihydroxyvitamin D₃；1,25-dihydroxyvitamin D₃；1,25(OH)₂D₃；1,25-dihydroxycholecalciferol；1,25-dihydroxyvitamin D；1α,25(OH)₂D₃；1α,25-dihydroxycholecalciferol；1a,25-dihydroxyvitamin D3；vitamin D；1,25D3；1alpha,25-Dihydroxyvitamin D3；1,25 dihydrocholecalciferol；calcitrol；1,25D；D1530；9,10-secocholesta-5,7,10(19)-triene-1α,3β,25-triol；(1R,3S,5Z)-5-[(2E)-2-[(1R,3aS,7aR)-1-[(2R)-6-hydroxy-6-methylheptan-2-yl]-7a-methyl-2,3,3a,5,6,7-hexahydro-1H-inden-4-ylidene]ethylidene]-4-methylidenecyclohexane-1,3-diol
• CAS: 32222-06-3
• 化学式: C₂₇H₄₄O₃
• 分子量: 416.645
• InChiKey: GMRQFYUYWCNGIN-NKMMMXOESA-N

物化性质

• 熔点：
  119-1210C
• 比旋光度：
  D25 +48° (methanol)
• 沸点：
  474.91°C (rough estimate)
• 密度：
  1.0362 (rough estimate)
• 闪点：
  14 °C
• 最大波长(λmax)：
  265nm(lit.)
• 物理描述：
  Solid
• 颜色/状态：
  Colorless, crystalline solid
• 溶解度：
  In water, 7.9X10-4 mg/L at 25 °C (est)
• 蒸汽压力：
  1.2X10-12 mm Hg at 25 °C (est)
• 稳定性/保质期：
  Calcitriol will degrade during prolonged exposure to light.
• 旋光度：
  Specific optical rotation = +48 deg at 22 °C/D (methanol)

计算性质

• 辛醇/水分配系数(LogP)：
  5.1
• 重原子数：
  30
• 可旋转键数：
  6
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.78
• 拓扑面积：
  60.7
• 氢给体数：
  3
• 氢受体数：
  3

ADMET

代谢

calcitriol的代谢涉及两条途径。第一条途径涉及肾脏中的24-羟基化酶活性；这种酶也存在于许多具有维生素D受体（如肠道）的目标组织中。这条途径的最终产物是侧链缩短的代谢物，即calcitroic酸。第二条途径涉及通过逐步羟基化碳-26和碳-23，然后环化，最终产生1a,25R(OH)2-26,23S-内酯D3，这似乎是人类循环中的主要代谢物。其他已知的calcitriol代谢物包括1α, 25(OH)2-24-氧代-D3；1α, 23,25(OH)3-24-氧代-D3；1α, 24R,25(OH)3D3；1α, 25S,26(OH)3D3；1α, 25(OH)2-23-氧代-D3；1α, 25R,26(OH)3-23-氧代-D3和1α, (OH)24,25,26,27-四去甲酸-D3。

Metabolism of calcitriol involves two pathways. The first pathway involves 24-hydroxylase activity in the kidney; this enzyme is also present in many target tissues which possess the vitamin D receptor such as the intestine. The end product of this pathway is a side chain shortened metabolite, calcitroic acid. The second pathway involves the conversion of calcitriol via the stepwise hydroxylation of carbon-26 and carbon-23, and cyclization to yield ultimately 1a,25R(OH)₂-26,23S-lactone D3, which appears to be the major metabolite circulating in humans. Ohter identified metabolites of calcitriol include 1α, 25(OH)2-24-oxo-D3; 1α, 23,25(OH)3-24-oxo-D3; 1α, 24R,25(OH)3D3; 1α, 25S,26(OH)3D3; 1α, 25(OH)2-23-oxo-D3; 1α, 25R,26(OH)3-23-oxo-D3 and 1α, (OH)24,25,26,27-tetranor-COOH-D3.

来源:DrugBank

代谢

钙三醇是维生素D3（胆钙化醇）的活性形式。人体内自然或内源性的维生素D供应主要依赖于紫外线，将皮肤中的7-脱氢胆固醇转化为维生素D3。维生素D3在肝脏和肾脏中必须经过代谢激活，才能在其靶组织中完全发挥作用。最初的转化由肝脏中的维生素D3-25-羟化酶酶催化，这个反应的产物是25-(OH)D3（钙化二醇）。后者在肾脏组织的线粒体中发生羟基化，这个反应由肾脏的25-羟基维生素D3-1α-羟化酶激活，以产生1,25-(OH)2D3（钙三醇），即维生素D3的活性形式。

Calcitriol is the active form of vitamin D3 (cholecalciferol). The natural or endogenous supply of vitamin D in man mainly depends on ultraviolet light for conversion of 7-dehydrocholesterol to vitamin D3 in the skin. Vitamin D3 must be metabolically activated in the liver and the kidney before it is fully active on its target tissues. The initial transformation is catalyzed by a vitamin D3-25-hydroxylase enzyme present in the liver, and the product of this reaction is 25-(OH)D3 (calcifediol). The latter undergoes hydroxylation in the mitochondria of kidney tissue, and this reaction is activated by the renal 25-hydroxyvitamin D3-1-a-hydroxylase to produce 1,25-(OH)2D3 (calcitriol), the active form of vitamin D3.

来源:Hazardous Substances Data Bank (HSDB)

代谢

1,25-二羟基胆固醇钙化醇（钙三醇）和1,25-二羟基麦角钙化醇似乎被代谢为它们各自的三羟基代谢物（即1,24,25-三羟基胆固醇钙化醇，1,24,25-三羟基麦角钙化醇）以及其他化合物。尿液中最主要的代谢物是更亲水的钙三醇酸。虽然尚未识别出胆固醇钙化醇和麦角钙化醇的所有代谢物，但肝脏微粒体酶可能参与降解麦角钙化醇和胆固醇钙化醇的代谢物。

1,25-Dihydroxycholecalciferol (calcitriol) and 1,25-dihydroxyergocalciferol appear to be metabolized to their respective trihydroxy metabolites (i.e., 1,24,25-trihydroxycholecalciferol, 1,24,25-trihydroxyergocalciferol) and to other compounds. The principal metabolite excreted in urine is calcitroic acid, which is more water soluble. Although all the metabolites of cholecalciferol and ergocalciferol have not been identified, hepatic microsomal enzymes may be involved in degrading metabolites of ergocalciferol and cholecalciferol.

来源:Hazardous Substances Data Bank (HSDB)

代谢

钙三醇（1,25-二羟基维生素D）通过一种由钙三醇诱导并由刺激25-OHD-1α-羟化酶的因素抑制的肾脏羟化酶转化为1,24,25-(OH)3-D。这种酶还使25-OHD羟基化形成24,25-(OH)2D。这两种24-羟基化合物比钙三醇活性低，可能代表注定要排泄的代谢物。钙三醇的侧链氧化也会发生。

Calcitriol /(1,25-dihydroxy-vitamin D)/ is hydroxylated to 1,24,25-(OH)3-D by a renal hydroxylase that is induced by calcitriol and suppressed by those factors that stimulate the 25-OHD-1-alpha-hydroxylase. This enzyme also hydroxylates 25-OHD to form 24,25-(OH)2D. Both 24-hydroxylated compounds are less active than calcitriol and presumably represent metabolites destined for excretion. Side chain oxidation of calcitriol also occurs.

来源:Hazardous Substances Data Bank (HSDB)

代谢

为了评估每日和禁食状态下尿钙排泄与血清1,25-二羟基维生素D（II）浓度之间的关系，对6名健康男性进行了研究，包括对照期和慢性口服钙三醇（I）给药期（每6小时0.6、1.2或1.8纳米摩尔，持续6-12天），同时他们食用正常和低钙饮食（19.2或4.2毫摩尔/天钙）。每日尿钙排泄与血清II浓度直接相关，但在食用正常钙饮食时比食用低钙饮食时增加更多。在I给药和低钙饮食期间，每日尿钙排泄平均为7.32毫摩尔/天，超过了饮食中钙的摄入量。禁食尿钙/肌酐在任何饮食上都超过了0.34毫摩尔/毫摩尔（正常的上限）。当血清II浓度升高时，即使是在低钙饮食上，高禁食尿钙/肌酐或高每日尿钙排泄也不足以证明肾钙漏的存在。

To evaluate the relation between daily and fasting urinary calcium excretion and serum 1,25-dihydroxyvitamin D (II) concentrations, 6 healthy men were studied during control and during chronic oral calcitrol (I) administration (0.6, 1.2, or 1.8 nmols every 6 hours for 6-12 days) while they ate normal and low calcium diets (19.2 or 4.2 mmols Ca/day). Daily urinary calcium excretion was directly related to serum II concentrations, but increased more while subjects ate the normal calcium diet than when eating the low calcium diet. During I and ingestion of the low calcium diet, daily urinary calcium excretion averaged 7.32 mmole/day, exceeding the dietary calcium intake. Fasting urinary calcium/creatinine exceeded 0.34 mmol/mmol (the upper limit of normal) on either diet. When serum II concentrations are elevated, a high fasting urinary calcium/creatinine or high daily urinary calcium excretion, even on a low calcium diet, is insufficient criteria for the documentation of a renal calcium leak.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 毒性总结

calcitriol治疗银屑病的机制是由于它们对角质形成细胞的抗增殖活性和对表皮细胞分化的刺激。活性形式的calcitriol的抗致癌活性似乎与细胞维生素D受体（VDR）水平有关。维生素D受体属于类固醇激素锌指受体的超家族。维生素D受体选择性地结合1,25-（OH）₂-D₃和视黄酸X受体（RXR）以形成与特定DNA序列相互作用的异二聚体复合物，这些DNA序列称为维生素D反应元件。维生素D受体是配体激活的转录因子。受体在结合其各自的配体时激活或抑制靶基因的转录。人们认为，calcitriol的抗致癌作用是通过癌细胞的维生素D受体（VDR）介导的。人们认为，calcitriol的免疫调节活性是通过在单核细胞中组成性表达但在T和B淋巴细胞激活时诱导的维生素D受体（VDR）介导的。1,25-（OH）₂-D₃还发现能增强某些维生素D受体阳性免疫细胞的活动，并提高某些靶细胞对免疫细胞分泌的各种细胞因子的敏感性。

The mechanism of action of calcitriol in the treatment of psoriasis is accounted for by their antiproliferative activity for keratinocytes and their stimulation of epidermal cell differentiation. The anticarcinogenic activity of the active form of Calcitriol appears to be correlated with cellular vitamin D receptor (VDR) levels. Vitamin D receptors belong to the superfamily of steroid-hormone zinc-finger receptors. VDRs selectively bind 1,25-(OH)₂-D3 and retinoic acid X receptor (RXR) to form a heterodimeric complex that interacts with specific DNA sequences known as vitamin D-responsive elements. VDRs are ligand-activated transcription factors. The receptors activate or repress the transcription of target genes upon binding their respective ligands. It is thought that the anticarcinogenic effect of Calcitriol is mediated via VDRs in cancer cells. The immunomodulatory activity of calcitriol is thought to be mediated by vitamin D receptors (VDRs) which are expressed constitutively in monocytes but induced upon activation of T and B lymphocytes. 1,25-(OH)₂-D3 has also been found to enhance the activity of some vitamin D-receptor positive immune cells and to enhance the sensitivity of certain target cells to various cytokines secreted by immune cells.

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 药物性肝损伤

化合物的名称: 骨化三醇

Compound:calcitriol

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

DILI 注解：无 DILI（药物性肝损伤）担忧

DILI Annotation:No-DILI-Concern

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

标签部分：没有匹配项

Label Section:No match

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

参考文献：M Chen, V Vijay, Q Shi, Z Liu, H Fang, W Tong. 美国食品药品监督管理局批准的药物标签用于研究药物诱导的肝损伤，《药物发现今日》，16(15-16):697-703, 2011. PMID:21624500 DOI:10.1016/j.drudis.2011.05.007 M Chen, A Suzuki, S Thakkar, K Yu, C Hu, W Tong. DILIrank：按人类发展药物诱导肝损伤风险排名的最大参考药物清单。《药物发现今日》2016, 21(4): 648-653. PMID:26948801 DOI:10.1016/j.drudis.2016.02.015

References:M Chen, V Vijay, Q Shi, Z Liu, H Fang, W Tong. FDA-Approved Drug Labeling for the Study of Drug-Induced Liver Injury, Drug Discovery Today, 16(15-16):697-703, 2011. PMID:21624500 DOI:10.1016/j.drudis.2011.05.007 M Chen, A Suzuki, S Thakkar, K Yu, C Hu, W Tong. DILIrank: the largest reference drug list ranked by the risk for developing drug-induced liver injury in humans. Drug Discov Today 2016, 21(4): 648-653. PMID:26948801 DOI:10.1016/j.drudis.2016.02.015

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

吸收、分配和排泄

• 吸收

给药后，钙三醇迅速从肠道吸收。当单次口服剂量为0.5微克钙三醇时，钙三醇的平均血清浓度从基线值40.0±4.4（标准差）皮克/毫升上升到2小时时的60.0±4.4皮克/毫升，然后在4小时下降到53.0±6.9，8小时时为50±7.0，12小时时为44±4.6，24小时时为41.5±5.1皮克/毫升。单次给药0.25至1.0微克钙三醇后，血浆峰浓度在3至6小时内达到。在一项药代动力学研究中，健康男性志愿者的口服生物利用度为70.6±5.8%，尿毒症男性患者的口服生物利用度为72.2±4.8%。

Upon administration, calcitriol is rapidly absorbed from the intestines. When a single oral dose of 0.5 mcg of calcitriol was administered, the mean serum concentrations of calcitriol rose from a baseline value of 40.0±4.4 (SD) pg/mL to 60.0±4.4 pg/mL at 2 hours, and declined to 53.0±6.9 at 4 hours, 50±7.0 at 8 hours, 44±4.6 at 12 hours and 41.5±5.1 at 24 hours. Following administration of single doses of 0.25 to 1.0 mcg of calcitriol, the peak plasma concentrations were reached within 3 to 6 hours. In a pharmacokinetic study, the oral bioavailability was 70.6±5.8% in healthy male volunteers and 72.2±4.8% in male patients with uraemia.

来源:DrugBank

吸收、分配和排泄

• 消除途径

在正常受试者中，大约27%和7%的放射性物质分别出现在24小时内的粪便和尿液中。钙三醇经历肠肝循环和胆汁排泄。钙三醇的代谢物主要在粪便中排泄。静脉注射放射性钙三醇后第六天的累积排泄量平均为尿液中16%，粪便中49%。

In normal subjects, approximately 27% and 7% of the radioactivity appeared in the feces and urine, respectively, within 24 hours. Calcitriol undergoes enterohepatic recycling and biliary excretion. The metabolites of calcitriol are excreted primarily in feces. Cumulative excretion of radioactivity on the sixth day following intravenous administration of radiolabeled calcitriol averaged 16% in urine and 49% in feces.

来源:DrugBank

吸收、分配和排泄

• 分布容积

静脉给药后，在健康男性志愿者中，骨化三醇的分布体积为0.49±0.14 L/kg，在参与药代动力学研究的尿毒症男性患者中为0.27±0.06 L/kg。有证据表明，骨化三醇以较低水平（即2.2±0.1 pg/mL）转移到人乳中。母体循环中的骨化三醇也可能进入胎儿循环。

Upon intravenous administration, the volume of distribution of calcitriol was 0.49±0.14 L/kg in healthy male volunteers and 0.27±0.06 l/kg in uraemic male patients participating in a pharmacokinetic study. There is some evidence that calcitriol is transferred into human milk at low levels (ie, 2.2±0.1 pg/mL) in mothers. Calcitriol from maternal circulation may also enter the fetal circulation.

来源:DrugBank

吸收、分配和排泄

• 清除

代谢清除率在健康男性志愿者中为23.5±4.34毫升/分钟，在患有尿毒症的男性患者中为10.1±1.35毫升/分钟。在接受腹膜透析的儿科患者中，给予10.2纳克/千克（标准差5.5纳克/千克）的剂量治疗2个月后，清除率为15.3毫升/小时/千克。

The metabolic clearance rate was 23.5±4.34 ml/min in healthy male volunteers and 10.1±1.35 ml/min in male patients with uraemia. In the pediatric patients undergoing peritoneal dialysis receiving dose of 10.2 ng/kg (SD 5.5 ng/kg) for 2 months, the clearance rate was 15.3 mL/hr/kg.

来源:DrugBank

吸收、分配和排泄

许多维生素D类似物在口服给药后，如果脂肪吸收正常，很容易从胃肠道吸收。胆汁的存在是吸收麦角钙化醇所必需的，患有肝脏、胆道或胃肠道疾病（例如，克罗恩病、惠普尔病、乳糜泻）的患者的胃肠道吸收程度可能会降低。因为维生素D是脂溶性的，它被并入乳糜微粒并通过淋巴系统吸收；大约80%摄入的维生素D似乎是通过这种机制被系统吸收的，主要在小肠。尽管一些证据表明，老年成年人对维生素D的肠道吸收可能会降低，但其他证据并未显示在治疗剂量下，维生素D的胃肠道吸收有临床重要的年龄相关性变化。目前尚不清楚衰老是否改变生理剂量的维生素D的胃肠道吸收。/维生素D类似物/

Many vitamin D analogs are readily absorbed from the GI tract following oral administration if fat absorption is normal. The presence of bile is required for absorption of ergocalciferol and the extent of GI absorption may be decreased in patients with hepatic, biliary, or GI disease (e.g., Crohn's disease, Whipple's disease, sprue). Because vitamin D is fat soluble, it is incorporated into chylomicrons and absorbed via the lymphatic system; approximately 80% of ingested vitamin D appears to be absorbed systemically through this mechanism, principally in the small intestine. Although some evidence suggested that intestinal absorption of vitamin D may be decreased in geriatric adults, other evidence did not show clinically important age-related alterations in GI absorption of the vitamin in therapeutic doses. It currently is not known whether aging alters the GI absorption of physiologic amounts of vitamin D. /Vitamin D analogs/

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 危险等级：
  6.1(a)
• 危险品标志：
  T+
• 安全说明：
  S36/37/39,S45
• 危险类别码：
  R26/27/28,R63
• WGK Germany：
  3
• 海关编码：
  2942000000
• 危险品运输编号：
  UN 2811 6.1/PG 1
• 危险类别：
  6.1(a)
• RTECS号：
  FZ4645000
• 包装等级：
  I
• 危险标志：
  GHS06
• 危险性描述：
  H300
• 危险性防范说明：
  P260,P262,P280,P301+P310+P330,P302+P352+P310,P304+P340+P310,P403+P233

制备方法与用途

二羟胆钙化醇

二羟胆钙化醇，即维生素1α，25-D3的重要活性代谢物，通常在肾脏内形成。近年来研究发现，除了肾脏外，胎盘、单核细胞、巨噬细胞、肿瘤细胞上清液、结节病患者淋巴结和角朊细胞中也存在1α羟化酶，能够产生钙三醇。

二羟胆钙化醇的前体是25-羟基胆钙化醇（阿法骨化醇）。该代谢物能促进小肠吸收钙并调节骨质中的无机盐转运等作用。

适应症

适用于慢性肾功能衰竭病人的肾性营养不良、甲状旁腺机能低下，维生素D依赖性佝偻病及抗维生素D佝偻病。

生理作用 钙三醇（骨化三醇）

钙三醇又名骨化三醇，是维生素D的活性形式，也是一种激素，在调节血钙与血磷浓度方面起重要作用。通过增加肠道的钙离子吸收来提高血液中的钙水平，并可增加骨中钙的释放以提高血钙水平。此研究由Michael F. Holick于1971年首次报道。

作用机制

钙三醇主要通过与其维生素D受体（VDR）结合发挥作用，如小肠上皮细胞胞质中的受体与钙三醇结合形成的配体-受体复合物转移到细胞核中作为促进钙结合蛋白的编码基因表达的转录因子。钙结合蛋白增加使细胞主动运输更多钙离子，从而提高钙吸收水平。同时，为维持电中性需要运输阴离子，主要是无机磷酸根离子，因此钙三醇也促进了磷的吸收。

临床应用

临床上可用于治疗低血钙症、甲状旁腺功能减退症（成人）、骨软化症、佝偻病（婴幼儿）、慢性肾脏病、肾性骨病及预防糖皮质激素引起的骨质疏松症。

生物活性

Calcitriol (RO215535, Topitriol, 1,25-Dihydroxyvitamin D3) 是维生素D的激素活性形式，是一种非选择性维生素D受体激活剂，对维生素D受体（VDR）的结合亲和力（IC50=0.4 nM）是选择性VDRA paricalcitol的10倍以上。建议现配现用。

靶点

• Target：vitamin D receptor (Cell-free assay)

体外研究

Calcitriol 是PHA诱导淋巴细胞增殖的有效抑制剂，在培养72小时后可抑制70％氚标记的胸腺嘧啶核苷掺入。它以浓度依赖性方式抑制PHA刺激的外周血单核细胞中白细胞介素-2（IL-2）的生产。Calcitriol 在5秒内增加细胞内钙离子浓度，通过从内质网和肌醇1,4,5-三磷酸肌醇及甘油二酯的形成动员钙。Calcitriol 能抑制人前列腺腺癌细胞增殖并促进其分化，选择性降低IV型胶原酶（MMP-2和MMP-9）的分泌水平。在鳞状细胞癌和前列腺癌中，Calcitriol 具有抗增殖活性，并增强基于铂的药物的抗肿瘤活性，在小鼠鳞状细胞癌及PC-3细胞中比paclitaxel更强。Calcitriol 作为多种恶性细胞类型的有效抗增殖剂，通过增加G0/G1期阻滞、诱导细胞凋亡和分化，调节生长因子受体表达发挥作用。它还能促进许多细胞毒性剂的抗肿瘤作用，并抑制肿瘤细胞的侵袭性和形成新血管。

用途

维生素类药，用于慢性肾功能衰竭患者的肾性骨营养不良。

类别

有毒物品

毒性分级

高毒

急性毒性

• 口服-大鼠 LD50：0.62毫克/公斤
• 口服-小鼠 LD50：1.35毫克/公斤

可燃性危险特性

可燃，火场排出辛辣刺激烟雾

储运特性

库房通风、低温干燥；与食品分开储运

灭火剂

水、砂土

反应信息

• 作为反应物：
  描述：

  骨化三醇 在 间氯过氧苯甲酸 作用下， 以 二氯甲烷 、 氯仿 为溶剂， 反应 2.5h， 生成
  参考文献：
  名称：

  一种骨化三醇的药物组合物

  摘要：

  本发明提供了一种新化合物杂质I，还提供了包含杂质I的骨化三醇药物组合物。通过限定骨化三醇药物组合物中杂质I的含量，使骨化三醇药物组合物的安全性得到提高，产品质量得到进一步保障。

  公开号：

  CN112552265A
• 作为产物：
  描述：

  阿法骨化醇 在 D-葡萄糖-6-磷酸 、 bovine adrenodoxin reductase 、 mouse 25-hydroxyvitamin D3 1α-hydroxylase 、 mouse adrenodoxin 、 水 、 还原型辅酶II(NADPH)四钠盐 、 glucose 6-phosphate dehydrogenase 作用下， 生成 骨化三醇
  参考文献：
  名称：

  小鼠25-羟基维生素D31α-羟化酶（CYP27B1）并入磷脂囊泡的底物的代谢

  摘要：

  CYP27B1催化25-羟基维生素D3的1α-羟基化为1α，25-二羟基维生素D3（维生素D3的激素活性形式）。为了进一步表征小鼠CYP27B1，它在大肠杆菌中表达，纯化并在掺入磷脂囊泡的底物上测量了其活性，磷脂囊泡是内部线粒体膜的模型。囊泡中的25-羟基维生素D3和25-羟基维生素D2以相似的动力学经历1α-羟基化，催化速率常数（k cat）分别为41和48 mol / min / mol P450，而K m值为5.9和4.6 mmol / min mol的磷脂分别。当膜中底物浓度大于K的4倍时，CYP27B1显示出抑制作用m，与25-羟基维生素D2相比，使用25-羟基维生素D3更明显。由二油酰基磷脂酰胆碱和心磷脂制备的囊泡中的催化效率高于二肉豆蔻酰基磷脂酰胆碱囊泡。CYP27B1也催化与囊泡相关的24 R的1α-羟基化，25-二羟基维生素D3和20-羟基维生素D3以及1α-羟基维生素D

  DOI：

  10.1016/j.jsbmb.2010.02.022
• 作为试剂：
  描述：

  、 、 骨化三醇 在 [26, 27-methyl-3H]1α,25-dihydroxyvitamin D3 、 乙醇 、 polypropylene 、 骨化三醇 、 磷酸肌酸 作用下， 以 1,4-二氧六环 为溶剂， 反应 2.0h， 生成 维生素 D3
  参考文献：
  名称：

  VITAMIN D3 LACTAM DERIVATIVE

  摘要：

  化合物式（1）或其药学上可接受的溶剂化物，可用于治疗或预防骨质疏松症、高钙血症、Paget病或哮喘。其中，（1）中R1代表C1-C6烷基或C7-C15芳基烷基（其芳环可以被C1-C6烷基、C1-C6甲氧基、羟基、卤原子或三氟甲基基团取代），R2代表C1-C6烷基，R3代表C1-C6烷基或烷氧基，可被羟基取代。

  公开号：

  US20110207944A1

文献信息

• [EN] INHIBITORS OF BRUTON'S TYROSINE KINASE<br/>[FR] INHIBITEURS DE TYROSINE KINASE DE BRUTON
  申请人：BIOCAD JOINT STOCK CO

  公开号：WO2018092047A1

  公开（公告）日：2018-05-24

  The present invention relates to a new compound of formula I: or pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: V1 is C or N, V2 is C(R2) or N, whereby if V1 is C then V2 is N, if V1 is C then V2 is C(R2), or if V1 is N then V2 is C(R2); each n, k is independently 0, 1; each R2, R11 is independently H, D, Hal, CN, NR'R", C(O)NR'R", C1-C6 alkoxy; R3 is H, D, hydroxy, C(O)C1-C6 alkyl, C(O)C2-C6 alkenyl, C(O)C2-C6 alkynyl, C1-C6 alkyl; R4 is H, Hal, CN, CONR'R", hydroxy, C1-C6 alkyl, C1-C6 alkoxy; L is CH2, NH, O or chemical bond; R1 is selected from the group of the fragments, comprising: Fragment 1, Fragment 2, Fragment 3 each A1, A2, A3, A4 is independently CH, N, CHal; each A5, A6, A7, A8, A9 is independently C, CH or N; R5 is H, CN, Hal, CONR'R", C1-C6 alkyl, non-substituted or substituted by one or more halogens; each R' and R" is independently selected from the group, comprising H, C1-C6 alkyl, C1-C6 cycloalkyl, aryl; R6 is selected from the group: [formula II] each R7, R8, R9, R10 is independently vinyl, methylacetylenyl; Hal is CI, Br, I, F, which have properties of inhibitor of Bruton's tyrosine kinase (Btk), to pharmaceutical compositions containing such compounds, and their use as pharmaceuticals for treatment of diseases and disorder.

  本发明涉及一种新的化合物，其化学式为I：或其药学上可接受的盐、溶剂化合物或立体异构体，其中：V1为C或N，V2为C(R2)或N，如果V1为C，则V2为N，如果V1为C，则V2为C(R2)，或者如果V1为N，则V2为C(R2)；每个n，k独立地为0或1；每个R2，R11独立地为H，D，Hal，CN，NR'R"，C(O)NR'R"，C1-C6烷氧基；R3为H，D，羟基，C(O)C1-C6烷基，C(O)C2-C6烯基，C(O)C2-C6炔基，C1-C6烷基；R4为H，Hal，CN，CONR'R"，羟基，C1-C6烷基，C1-C6烷氧基；L为CH2，NH，O或化学键；R1从包括的片段组中选择：片段1，片段2，片段3，每个A1，A2，A3，A4独立地为CH，N，CHal；每个A5，A6，A7，A8，A9独立地为C，CH或N；R5为H，CN，Hal，CONR'R"，C1-C6烷基，未取代或被一个或多个卤素取代；每个R'和R"独立地从包括H，C1-C6烷基，C1-C6环烷基，芳基的组中选择；R6从组中选择：[化学式II]每个R7，R8，R9，R10独立地为乙烯基，甲基乙炔基；Hal为CI，Br，I，F，具有布鲁顿酪氨酸激酶（Btk）抑制剂的性质，以及含有这种化合物的药物组合物，以及它们作为治疗疾病和紊乱的药物的用途。
• [EN] BRUTON'S TYROSINE KINASE INHIBITORS<br/>[FR] INHIBITEURS DE LA TYROSINE KINASE DE BRUTON
  申请人：PFIZER

  公开号：WO2014068527A1

  公开（公告）日：2014-05-08

  Disclosed herein are compounds that form covalent bonds with Bruton's tyrosine kinase (BTK). Methods for the preparation of the compounds are disclosed. Also disclosed are pharmaceutical compositions that include the compounds. Methods of using the BTK inhibitors are disclosed, alone or in combination with other therapeutic agents, for the treatment of autoimmune diseases or conditions, heteroimmune diseases or conditions, cancer, including lymphoma, and inflammatory diseases or conditions. (Formula I)

  本文披露了一种与Bruton's酪氨酸激酶（BTK）形成共价键的化合物。公开了制备这些化合物的方法。还披露了包括这些化合物的药物组合物。公开了使用BTK抑制剂的方法，单独或与其他治疗剂联合治疗自身免疫疾病或症状、异源免疫疾病或症状、癌症，包括淋巴瘤，以及炎症性疾病或症状的方法。 (化学式I)
• [EN] FUSED PYRAZOLE DERIVATIVES AS JAK INHIBITORS<br/>[FR] DÉRIVÉS DE PYRAZOLE CONDENSÉS UTILISÉS EN TANT QU'INHIBITEURS DE JAK
  申请人：ALMIRALL SA

  公开号：WO2017220431A1

  公开（公告）日：2017-12-28

  Novel fused pyrazole derivatives of Formula (I) are disclosed; as well as process for their preparation, pharmaceutical compositions comprising them and their use in therapy as inhibitors of Janus Kinases (JAK).

  公开了式（I）的新型融合吡唑衍生物；以及它们的制备方法，包含它们的药物组合物以及它们作为Janus激酶（JAK）抑制剂在治疗中的用途。
• BRM TARGETING COMPOUNDS AND ASSOCIATED METHODS OF USE
  申请人：Arvinas Operations, Inc.

  公开号：US20190300521A1

  公开（公告）日：2019-10-03

  The present disclosure relates to bifunctional compounds, which find utility as modulators of SMARCA2 or BRM (target protein). In particular, the present disclosure is directed to bifunctional compounds, which contain on one end a ligand that binds to the Von Hippel-Lindau E3 ubiquitin ligase, and on the other end a moiety which binds the target protein, such that the target protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of target protein. The present disclosure exhibits a broad range of pharmacological activities associated with degradation/inhibition of target protein. Diseases or disorders that result from aggregation or accumulation of the target protein are treated or prevented with compounds and compositions of the present disclosure.

  本公开涉及双功能化合物，其作为SMARCA2或BRM（靶蛋白）的调节剂具有实用性。具体而言，本公开涉及包含一端结合Von Hippel-Lindau E3泛素连接酶的配体，另一端结合靶蛋白的双功能化合物，使得靶蛋白与泛素连接酶靠近以实现靶蛋白的降解（和抑制）。本公开展示了与靶蛋白降解/抑制相关的广泛药理活性。本公开的化合物和组合物用于治疗或预防由靶蛋白聚集或积累导致的疾病或紊乱。
• [EN] PROCESSES FOR MAKING TRIAZOLO[4,5D] PYRAMIDINE DERIVATIVES AND INTERMEDIATES THEREOF<br/>[FR] PROCÉDÉS DE PREPARATION DE DÉRIVÉS DE TRIAZOLO [4,5 D] PYRIMIDINE ET INTERMÉDIAIRES DE CEUX-CI
  申请人：CORVUS PHARMACEUTICALS INC

  公开号：WO2018183965A1

  公开（公告）日：2018-10-04

  Provided herein are, inter alia, methods for making triazolo[4,5]pyramidine derivatives and intermediates thereof that are useful for treating diseases.

  本文提供了制备三氮杂[4,5]吡啶衍生物及其中间体的方法，这些衍生物对治疗疾病有用。