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纳摩尔和10纳摩尔。

反应信息

• 作为反应物：
  描述：

  tenapanor 在 氢溴酸 作用下， 以 四氢呋喃 、 水 为溶剂， 反应 24.0h， 生成
  参考文献：
  名称：

  [EN] SOLID FORMS OF TENAPANOR AND METHOD OF PREPARATION OF TENAPANOR
  [FR] FORMES SOLIDES DE TÉNAPANOR ET PROCÉDÉ DE PRÉPARATION DE TÉNAPANOR

  摘要：

  该发明涉及特纳帕诺的固体形式，特别是特纳帕诺游离碱的结晶形式I和固体特纳帕诺盐，以及其制备方法。结晶形式I是已知的特纳帕诺的第一种结晶形式。特纳帕诺的新型固体形式可用于特纳帕诺的纯化和/或在制药组合物中使用。此外，该发明提供了一种经济有效且可扩展的结晶特纳帕诺的制备方法。

  公开号：

  WO2019091503A1
• 作为产物：
  描述：

  (S)-tert-butyl (2-(2-(2-(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonamido)ethoxy)ethoxy)ethyl)carbamate 在 盐酸 、 三乙胺 作用下， 以 二氯甲烷 、 水 为溶剂， 反应 2.0h， 生成 tenapanor
  参考文献：
  名称：

  [EN] SOLID FORMS OF TENAPANOR AND METHOD OF PREPARATION OF TENAPANOR
  [FR] FORMES SOLIDES DE TÉNAPANOR ET PROCÉDÉ DE PRÉPARATION DE TÉNAPANOR

  摘要：

  该发明涉及特纳帕诺的固体形式，特别是特纳帕诺游离碱的结晶形式I和固体特纳帕诺盐，以及其制备方法。结晶形式I是已知的特纳帕诺的第一种结晶形式。特纳帕诺的新型固体形式可用于特纳帕诺的纯化和/或在制药组合物中使用。此外，该发明提供了一种经济有效且可扩展的结晶特纳帕诺的制备方法。

  公开号：

  WO2019091503A1

文献信息

• [EN] PROCESSES FOR THE PREPARATION OF TENAPANOR AND INTERMEDIATES THEREOF<br/>[FR] PROCÉDÉS POUR LA PRÉPARATION DE TÉNAPANOR ET D'INTERMÉDIAIRES DE CEUX-CI
  申请人：TEVA PHARMACEUTICALS INT GMBH

  公开号：WO2020051014A1

  公开（公告）日：2020-03-12

  The present invention provides new procedures and intermediates for the preparation of Tenapanor, Tenapanor dihydrochloride and solid state forms thereof.

  本发明提供了制备Tenapanor、Tenapanor双盐酸盐及其固态形式的新工艺和中间体。
• 一种坦帕诺的制备方法
  申请人：山东汇海医药化工有限公司

  公开号：CN112047881B

  公开（公告）日：2023-04-11

  本发明公开了一种坦帕诺的制备方法，属于医药领域。该方法以(S)‑4‑(3‑溴苯基)‑6,8‑二氯‑2‑甲基＝1,2，3,4‑四氢异喹啉为原料，制成格氏试剂后直接与二氧化硫反应得到亚磺酸盐中间体，不经分离纯化直接与化合物2在次氯酸钠和醋酸的作用下得到坦帕诺；操作简便，反应周期短，大大减少了人工成本；此路线避免了使用剧毒试剂苄硫醇和氯气，减少了人员伤害，更为环保；避免了使用昂贵的钯催化剂，降低了生产成本；更适合工业化生产。
• COMPOUNDS AND METHODS FOR INHIBITING NHE-MEDIATED ANTIPORT IN THE TREATMENT OF DISORDERS ASSOCIATED WITH FLUID RETENTION OR SALT OVERLOAD AND GASTROINTESTINAL TRACT DISORDERS
  申请人：Charmot Dominique

  公开号：US20120263670A1

  公开（公告）日：2012-10-18

  The present disclosure is directed to compounds and methods for the treatment of disorders associated with fluid retention or salt overload, such as heart failure (in particular, congestive heart failure), chronic kidney disease, end-stage renal disease, liver disease, and peroxisome proliferator-activated receptor (PPAR) gamma agonist-induced fluid retention. The present disclosure is also directed to compounds and methods for the treatment of hypertension. The present disclosure is also directed to compounds and methods for the treatment of gastrointestinal tract disorders, including the treatment or reduction of pain associated with gastrointestinal tract disorders.

  本公开涉及化合物和方法，用于治疗与液体潴留或盐过载相关的疾病，如心力衰竭（特别是充血性心力衰竭）、慢性肾脏病、终末期肾脏病、肝病和过氧化物酶体增殖物激活受体（PPAR）γ激动剂引起的液体潴留。本公开还涉及化合物和方法，用于治疗高血压。本公开还涉及化合物和方法，用于治疗胃肠道疾病，包括治疗或减轻与胃肠道疾病相关的疼痛。
• COMPOUNDS AND METHODS FOR INHIBITING NHE-MEDIATED ANTIPORT IN THE TREATMENT OF DISORDERS ASSOCIATED WITH FLUID RETENTION OR SALT OVERLOAD AND GASTROINTESTINAL TRACT DISORDER
  申请人：Ardelyx, Inc.

  公开号：US20150190389A1

  公开（公告）日：2015-07-09

  The present disclosure is directed to compounds of the structure (X): CoreL-NHE) n (X) wherein: n is 2 or 3; NHE has the structure wherein: R 1 is H or —SO 2 —NR 7 R 8 —; R 2 is selected from H, —NR 7 (CO)R 8 , —SO 2 —NR 7 R 8 — and —NR 7 R 8 ; R 3 is hydrogen; R 7 is hydrogen; R 8 is a bond linking to L; L is a polyalkylene glycol linker; and Core has the following structure: wherein: X is selected from the group consisting of a bond, —O—, —NH—, NHC(═O)—, —NHC(═O)NH— and —NHSO 2 —; and Y is selected from the group consisting of a bond, optionally substituted C 1-6 alkylene, optionally substituted benzene, pyridinyl, a polyethylene glycol linker and —(CH 2 ) 1-6 O(CH 2 ) 1-6 —, and methods of using such compounds for the treatment of irritable bowel syndrome, chronic kidney disease and end-stage renal disease.

  本公开涉及结构为（X）：CoreL-NHE)n（X）的化合物，其中：n为2或3；NHE具有以下结构：其中：R1为H或—SO2—NR7R8—；R2选自H，—NR7（CO）R8，—SO2—NR7R8—和—NR7R8；R3为氢；R7为氢；R8为连接到L的键；L为多聚乙二醇连接剂；Core具有以下结构：其中：X选自由键，—O—，—NH—，NHC（═O）—，—NHC（═O）NH—和—NHSO2—；Y选自键，可选择性地取代的C1-6烷基，可选择性地取代的苯，吡啶基，聚乙二醇连接剂和—（CH2）1-6O（CH2）1-6—，以及使用这种化合物治疗肠易激综合征、慢性肾脏病和终末期肾脏疾病的方法。
• COMBINATIONS FOR INHIBITING NHE-MEDIATED ANTIPORT IN THE TREATMENT OF DISORDERS ASSOCIATED WITH FLUID RETENTION OR SALT OVERLOAD AND GASTROINTESTINAL TRACT DISORDERS
  申请人：Ardelyx, Inc.

  公开号：EP3939964A1

  公开（公告）日：2022-01-19

  The present disclosure is directed to a pharmaceutical composition comprising a compound of formula (X), in combination with another active agent, and to the use of said composition in methods for the treatment of disorders associated with fluid retention or salt overload or gastrointestinal tract disorders, such as irritable bowel syndrome and constipation associated with cystic fibrosis. The methods generally comprise administering to a mammal in need thereof a pharmaceutical composition comprising such a compound, that is designed to be substantially active in the gastrointestinal (GI) tract to inhibit NHE-mediated antiport of sodium ions and hydrogen ions therein. More particularly, the method comprises administering to a mammal in need thereof a pharmaceutical composition comprising such a compound, that inhibits NHE-3, -2 and/or -8 mediated antiport of sodium and/or hydrogen ions in the GI tract and is designed to be substantially impermeable to the layer of epithelial cells, or more specifically the epithelium of the GI tract. As a result of the compound being substantially impermeable, it is not absorbed and is thus essentially systemically non-bioavailable, so as to limit the exposure of other internal organs (e.g., liver, heart, brain, etc.) thereto.

  本公开涉及一种药物组合物，该组合物包含与另一种活性剂组合的式(X)化合物，并涉及将所述组合物用于治疗与体液潴留或盐超载相关的疾病或胃肠道疾病（如肠易激综合征和与囊性纤维化相关的便秘）的方法。这些方法一般包括向有需要的哺乳动物施用包含此类化合物的药物组合物，该组合物设计为在胃肠道（GI）中基本活跃，以抑制其中钠离子和氢离子的 NHE 介导的反转运。更具体地说，该方法包括向有需要的哺乳动物施用包含这种化合物的药物组合物，该化合物可抑制胃肠道中NHE-3、-2和/或-8介导的钠离子和/或氢离子的反转运，并且设计成基本上不渗透到上皮细胞层，或更具体地说，不渗透到胃肠道上皮细胞层。由于该化合物基本上不渗透，因此不会被吸收，从而基本上不会被全身生物利用，从而限制了其他内脏器官（如肝脏、心脏、大脑等）对该化合物的接触。