2-Propen-1-one, 2-[(dimethylamino)methyl]-1-(2,4-dimethylphenyl)- | 116218-49-6

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: 2-Propen-1-one, 2-[(dimethylamino)methyl]-1-(2,4-dimethylphenyl)-
• 英文别名: 2-[(dimethylamino)methyl]-1-(2,4-dimethylphenyl)prop-2-en-1-one
• CAS: 116218-49-6
• 化学式: C₁₄H₁₉NO
• 分子量: 217.31
• InChiKey: QXLQZLBNPTZMRK-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.8
• 重原子数：
  16
• 可旋转键数：
  4
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.36
• 拓扑面积：
  20.3
• 氢给体数：
  0
• 氢受体数：
  2

ADMET

代谢

天冬酰胺酶的代谢命运尚不清楚；只有微量的剂量出现在尿液中。

The metabolic fate of asparaginase is not known; only trace amounts of a dose appear in the urine.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 药物性肝损伤

化合物：培加斯帕酶

Compound:pegaspargase

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

药物性肝损伤标注：低药物性肝损伤关注

DILI Annotation:Less-DILI-Concern

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

严重性等级：3

Severity Grade:3

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

“标签部分：不良反应”

Label Section:Adverse reactions

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

氨基酸缺失的初始阶段在4天内通过肌内注射发生，达到峰值的时间：肌内注射为3到4天。

Onset of Asparagine depletion by IM is within 4 days Time to peak: IM: 3 to 4 days

来源:DrugBank

吸收、分配和排泄

• 分布容积

IV: 成人（未曾使用过天冬酰胺酶的患者）: 2.4 L/m2 分布到脑脊液（据报道，与天冬酰胺酶相似，能将脑脊液中的天冬酰胺浓度降低到相似的程度）

IV: Adults (asparaginase naive): 2.4 L/m2 Distributes into CSF (reportedly reducing CSF asparagine concentrations to a similar extent as asparaginase

来源:DrugBank

吸收、分配和排泄

天冬酰胺酶不从胃肠道吸收，因此必须通过非胃肠道途径给药。重复给予天冬酰胺酶最初会产生累积血浆浓度，在几次剂量后达到平稳。在一项研究中，每天给药前测得的最大平稳血清浓度在儿童平均为14.5单位/mL，在成人平均为26.7单位/mL，他们每天通过静脉注射1000单位/千克的天冬酰胺酶。使用每天5000单位/千克的静脉注射剂量，最大平稳血清浓度在儿童平均为50单位/mL，在成人平均为70单位/mL。在一例患者中，隔天肌内注射后的平稳血浆浓度略低于每天静脉注射后的浓度。在某些患者中，尽管持续给药，血浆天冬酰胺酶浓度仍会下降。在停止每天天冬酰胺酶治疗后，可测得的药物血浆浓度可持续长达22天。

Asparaginase is not absorbed from the GI tract and therefore must be administered parenterally. Repeated administration of asparaginase initially produces cumulative plasma concentrations which plateau after several doses. In one study, maximum plateau serum concentrations measured just prior to the daily dose averaged 14.5 units/mL in children and 26.7 units/mL in adults given 1000 units of asparaginase per kg iv daily. With iv doses of 5000 units/kg daily, maximum plateau serum concentrations averaged 50 units/mL in children and 70 units/mL in adults. In one patient, plateau plasma concentrations following alternate-day im administration were slightly less than half those following daily iv administration. In some patients, plasma asparaginase concentrations decrease despite continued administration of the drug. Measurable plasma concentrations of the drug persist for up to 22 days after discontinuing daily asparaginase therapy.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

在给予初始静脉注射天门冬酰胺酶后，如果没有出现耐药性，血液中的天门冬酰胺浓度几乎会立即下降到无法检测到的水平，并且在治疗持续期间保持不可测量。治疗停止后，天门冬酰胺在大约23-33天内重新出现在血浆中。血液中的谷氨酰胺浓度在天门冬酰胺酶治疗开始后也会降至无法检测的水平，并在治疗停止后开始恢复正常。在一项研究中，接受天门冬酰胺酶维持剂量（每天10-50单位/千克）治疗的患者中，谷氨酰胺（而不是天门冬酰胺）浓度恢复正常。

Following an initial iv dose of asparaginase, if resistance does not occur, blood asparagine concentrations fall almost immediately to undetectable concentrations and remain unmeasurable as long as therapy is continued. Following cessation of therapy, asparagine reappears in the plasma within 23-33 days. Blood glutamine concentrations also fall to undetectable concentrations after initiation of asparaginase therapy and begin to return to normal when therapy is discontinued. In one study, glutamine (but not asparagine) concentrations returned to normal in patients receiving asparaginase maintenance dosages of 10-50 units/kg daily.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

在一项针对转移性癌症和白血病患者的研究中，每天静脉注射L-天冬酰胺酶导致血浆中水平累积增加。分布容积略大于血浆体积。脑脊液中的天冬酰胺酶水平低于同期血浆水平的1%。

In a study in patients with metastatic cancer and leukemia, daily intravenous administration of L-asparaginase resulted in a cumulative increase in plasma levels. ... Apparent volume of distribution was slightly greater than the plasma volume. Asparaginase levels in cerebrospinal fluid were less than 1% of concurrent plasma levels.

来源:Hazardous Substances Data Bank (HSDB)

文献信息

• REPROGRAMMING EFFECTOR PROTEIN INTERACTIONS TO CORRECT EPIGENETIC DEFECTS IN CANCER
  申请人：British Columbia Cancer Agency Branch

  公开号：EP2819662B1

  公开（公告）日：2019-04-10
• US9552457B2
  申请人：——

  公开号：US9552457B2

  公开（公告）日：2017-01-24
• [EN] REPROGRAMMING EFFECTOR PROTEIN INTERACTIONS TO CORRECT EPIGENETIC DEFECTS IN CANCER<br/>[FR] REPROGRAMMATION D'INTERACTIONS ENTRE PROTÉINES EFFECTRICES POUR CORRIGER DES DÉFAUTS ÉPIGÉNÉTIQUES DANS LE CANCER
  申请人：BRITISH COLUMBIA CANCER AGENCY

  公开号：WO2013127011A1

  公开（公告）日：2013-09-06

  Methods of "reprogramming" epigenetic mark readers or erasers to recognize epigenetic marks other than their cognate (or natural) marks are provided. Reprogramming the reader or eraser can offset the effects of aberrant writer activity (for example, loss of function or overactivity) that can contribute to certain diseases states, such as cancer. The use of the reprogramming compounds identified by these methods in the treatment of such disease states is also provided. Exemplary mark readers that can be targeted by these methods include BPTF and CBX2.