tenapanor | 1234423-95-0

• 物质功能分类: 生物化工 - 生化试剂 - 激动剂抑制剂
• 分子结构分类: 有机化合物 - 有机杂环化合物 - 四氢异喹啉
• 英文名称: tenapanor
• 英文别名: 3-((S)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)-N-(26-((3-((S)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenyl)sulfonamido)-10,17-dioxo-3,6,21,24-tetraoxa-9,11,16,18-tetraazahexacosyl)benzenesulfonamide；Tenapanor；1-[2-[2-[2-[[3-[(4S)-6,8-dichloro-2-methyl-3,4-dihydro-1H-isoquinolin-4-yl]phenyl]sulfonylamino]ethoxy]ethoxy]ethyl]-3-[4-[2-[2-[2-[[3-[(4S)-6,8-dichloro-2-methyl-3,4-dihydro-1H-isoquinolin-4-yl]phenyl]sulfonylamino]ethoxy]ethoxy]ethylcarbamoylamino]butyl]urea
• CAS: 1234423-95-0
• 化学式: C₅₀H₆₆Cl₄N₈O₁₀S₂
• mdl: MFCD28386333
• 分子量: 1145.07
• InChiKey: DNHPDWGIXIMXSA-CXNSMIOJSA-N

物化性质

• 溶解度：
  DMSO：50 mg/mL (43.67 mM)；水：< 0.1 mg/mL（不溶）

计算性质

• 辛醇/水分配系数(LogP)：
  5.1
• 重原子数：
  74
• 可旋转键数：
  29
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.48
• 拓扑面积：
  235
• 氢给体数：
  6
• 氢受体数：
  14

ADMET

代谢

替那帕诺的主要代谢物M1，大部分是通过CYP3A4/5酶催化的。由于替那帕诺的系统性吸收极少，它对肝脏CYP酶的暴露可能有限，因此其代谢可能是由肠道CYP酶活性引起的。替那帕诺的M1代谢物是P-糖蛋白的底物，与母药相比，可以在血浆中检测到，达到稳态时Cmax约为15 ng/mL。它不被认为是针对NHE3的活性物质。

The majority of tenapanor's metabolism to its primary metabolite, M1, is catalyzed via CYP3A4/5. Exposure of tenapanor to hepatic CYP enzymes is likely limited due to its minimal systemic absorption, so its metabolism may be due to intestinal CYP enzyme activity. The M1 metabolite of tenapanor is a P-glycoprotein substrate and, in contrast to its parent drug, can be detected in plasma, reaching a C_max of approximately 15 ng/mL at steady state. It is not considered active against NHE3.

来源:DrugBank

毒理性

• 毒性总结

过量症状可能与tenapanor的不良反应特征一致，因此可能包括如腹泻等胃肠道效应。脱水可能会根据腹泻的持续时间和严重程度而发生。在过量情况下，尚未提出特定的管理策略。

Symptoms of overdose are likely to be consistent with tenapanor's adverse effect profile, and may therefore include gastrointestinal effects such as diarrhea. Dehydration may occur depending on duration and severity of diarrhea. No specific management strategies have been proposed in cases of overdose.

来源:DrugBank

毒理性

• 蛋白质结合

替那帕诺及其主要代谢物M1在大约99%和97%的程度上高度与血浆蛋白结合，具体与替那帕诺及其代谢物结合的蛋白尚未阐明。

Both tenapanor and its principle metabolite, M1, are highly plasma protein bound at approximately 99% and 97%, respectively. The specific proteins to which tenapanor and its metabolite binds have yet to be elucidated.

来源:DrugBank

吸收、分配和排泄

• 吸收

在临床研究中，健康受试者的大部分样本中的血浆浓度低于定量限（即小于0.5 ng/mL），因此无法确定与吸收相关的典型药代动力学值，如AUC和Cmax。饭前5到10分钟给药时，tenapanor的效果最佳。

Tenapanor undergoes very minimal systemic absorption following oral administration. During clinical trials, plasma concentrations were below the limit of quantitation (i.e. less than 0.5 ng/mL) in the majority of samples from healthy subjects - for this reason, typical pharmacokinetic values related to absorption such as AUC and C_max were unable to be ascertained. The effects of tenapanor are greatest when administered 5 to 10 minutes before meals.

来源:DrugBank

吸收、分配和排泄

• 消除途径

在给予tenapanor的放射性标记剂量后，70%的放射性在给药后120小时内通过粪便排出，240小时内排出79%。大约65%的总剂量在144小时内以未变化的母药形式排出。只有9%的给药剂量在尿液中找到，主要是以代谢物的形式存在。Tenapanor的M1代谢物以未变化的形式在尿液中排出，占给药后144小时内总剂量的约1.5%。

Following administration of a radio labeled dose of tenapanor, 70% of the radioactivity was excreted in the feces within 120 hours of administration and 79% within 240 hours. Approximately 65% of the total dose is excreted as unchanged parent drug within 144 hours of administration. Only 9% of the administered dose was found in the urine, existing primarily as metabolites. Tenapanor's M1 metabolite is excreted unchanged in the urine and accounts for approximately 1.5% of the total dose within 144 hours of administration.

来源:DrugBank

安全信息

• 危险性防范说明：
  P261,P305+P351+P338
• 危险性描述：
  H302,H315,H319,H335
• 储存条件：
  2-8℃

制备方法与用途

Tenapanor是一种钠氢离子交换NHE3的抑制剂，能够抑制人类和大鼠NHE3的活性，其抑制浓度分别为5纳摩�