6-[7(R)-羟基-6,7-二氢-5H-吡咯并[1,2-C]咪唑-7-基]-N-甲基-2-萘甲酰胺 | 752243-39-3

• 分子结构分类: 有机化合物 - 苯类化合物 - 萘
• 中文名称: 6-[7(R)-羟基-6,7-二氢-5H-吡咯并[1,2-C]咪唑-7-基]-N-甲基-2-萘甲酰胺
• 英文名称: orteronel
• 英文别名: (R)-orteronel；Orteronel, (R)-；6-[(7R)-7-hydroxy-5,6-dihydropyrrolo[1,2-c]imidazol-7-yl]-N-methylnaphthalene-2-carboxamide
• CAS: 752243-39-3
• 化学式: C₁₈H₁₇N₃O₂
• 分子量: 307.352
• InChiKey: OZPFIJIOIVJZMN-GOSISDBHSA-N

物化性质

• 密度：
  1.35
• 溶解度：
  溶于二甲基亚砜

计算性质

• 辛醇/水分配系数(LogP)：
  1.3
• 重原子数：
  23
• 可旋转键数：
  2
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.22
• 拓扑面积：
  67.2
• 氢给体数：
  2
• 氢受体数：
  3

反应信息

• 作为产物：
  描述：

  orteronel 以 甲醇 、 水 为溶剂， 生成 Orteronel; 6-[(7S)-7-羟基-6,7-二氢-5H-吡咯并[1,2-c]咪唑-7-基]-N-甲基-2-萘甲酰胺 、 6-[7(R)-羟基-6,7-二氢-5H-吡咯并[1,2-C]咪唑-7-基]-N-甲基-2-萘甲酰胺
  参考文献：
  名称：

  人类细胞色素P450 17A1孕酮和孕烯醇酮两步氧化为雄激素的动力学过程。

  摘要：

  细胞色素P450（P450，CYP）17A1在类固醇代谢中起关键作用，催化孕烯醇酮和孕酮的17α-羟基化以及随后的17α，20-裂合酶反应分别形成脱氢表雄酮（DHEA）和雄烯二酮（Andro）至关重要用于产生糖皮质激素和雄激素。辅助蛋白细胞色素b5（b5）可提高检测到的人P450 17A1反应速率，但尚不清楚b5在P450 17A1催化的反应中的确切作用，以及这些反应的一些细节。在这里，我们详细检查了17α-羟基化和裂解酶步骤的生产力。b5不能通过降低任何类固醇的koff速率来提高反应速率。类固醇与P450 17A1的结合比简单的两态系统复杂。稳态前的实验表明黄体酮产生雄激素和孕烯醇酮产生脱氢表雄酮的滞后阶段，表明该酶的分布特征。但是，我们在孕烯醇酮/ DHEA脉冲追踪实验中观察到了持续性。（S）-Orteronel对17α-羟基孕烯醇酮转化为DHEA的抑制作用是对孕烯醇酮的17α-羟基化

  DOI：

  10.1074/jbc.m117.794917

文献信息

• PHARMACEUTICAL COMPOSITION AND APPLICATION THEREOF
  申请人：Kangpu Biopharmaceuticals, Ltd.

  公开号：EP3357513A1

  公开（公告）日：2018-08-08

  Disclosed are a pharmaceutical composition and an application thereof. The pharmaceutical composition includes one or more of a benzoheterocyclic compound as shown in formula (I), a pharmaceutically acceptable salt thereof, a solvate thereof, a crystalline form thereof, a co-crystal thereof, a stereoisomer thereof, an isotope compound thereof, a metabolite thereof and a prodrug thereof, and an androgen receptor pathway modulator. The pharmaceutical composition better inhibits prostate cancer cell growth.

  公开了一种药物组合物及其应用。该药物组合物包括一种或多种如式（I）所示的苯并杂环化合物、其药学上可接受的盐、其溶液、其晶体、其共晶体、其立体异构体、其同位素化合物、其代谢物和其原药，以及雄激素受体通路调节剂。该药物组合物能更好地抑制前列腺癌细胞的生长。
• COMPOSITION, APPLICATION THEREOF AND TREATMENT METHOD
  申请人：Kangpu Biopharmaceuticals, Ltd.

  公开号：EP3527210A1

  公开（公告）日：2019-08-21

  Provided are a combination, an application thereof and a treatment method. The combination comprises one or more of a benzoheterocyclic compound of formula (I), a pharmaceutically acceptable salt, a solvate, a crystalline form, a cocrystal, a stereoisomer, an isotope compound, a metabolite and a prodrug thereof, and an androgen receptor pathway modulator and/or a hormone drug. The combination and treatment method may effectively inhibit the growth of prostate cancer cells.

  本文提供了一种组合物、其应用和治疗方法。该组合物包括一种或多种式（I）的苯并杂环化合物、药学上可接受的盐、溶液、结晶体、共晶体、立体异构体、同位素化合物、其代谢物和原药，以及雄激素受体通路调节剂和/或激素药物。这种组合和治疗方法可有效抑制前列腺癌细胞的生长。
• Combination, application thereof and treatment method
  申请人：KANGPU BIOPHARMACEUTICALS, LTD.

  公开号：US10933059B2

  公开（公告）日：2021-03-02

  Provided are a combination, an application thereof and a treatment method. The combination comprises one or more of a benzoheterocyclic compound of formula (I), a pharmaceutically acceptable salt, a solvate, a crystalline form, a cocrystal, a stereoisomer, an isotope compound, a metabolite and a prodrug thereof, and an androgen receptor pathway modulator and/or a hormone drug. The combination and treatment method may effectively inhibit the growth of prostate cancer cells.

  本文提供了一种组合物、其应用和治疗方法。该组合物包括一种或多种式（I）的苯并杂环化合物、药学上可接受的盐、溶液、结晶体、共晶体、立体异构体、同位素化合物、其代谢物和原药，以及雄激素受体通路调节剂和/或激素药物。这种组合和治疗方法可有效抑制前列腺癌细胞的生长。
• Multistep Binding of the Non-Steroidal Inhibitors Orteronel and Seviteronel to Human Cytochrome P450 17A1 and Relevance to Inhibition of Enzyme Activity
  作者：Stella A. Child、F. Peter Guengerich

  DOI：10.1021/acs.jmedchem.9b01849

  日期：2020.6.25

  Orteronel (TAK-700) is a substituted imidazole that was developed for the treatment of castration-resistant prostate cancer but was dropped in phase III clinical trials. Both enantiomers of this inhibitor of cytochrome P450 (P450) 17A1 show some selectivity in differentially blocking the 17α-hydroxylation and lyase activities of the enzyme. Although both enantiomers of this compound have sub-micromolar

  Orteronel（TAK-700）是一种取代的咪唑，开发用于治疗去势抵抗性前列腺癌，但在III期临床试验中被放弃。该细胞色素P450（P450）17A1抑制剂的两种对映异构体在差异性阻断酶的17α-羟基化和裂解酶活性方面均表现出一定的选择性。尽管该化合物的两种对映异构体均具有亚微摩尔IC 50值，并以II型光谱变化（指示氮铁键合）结合到酶上，并且K d值分别为56和40 nM（R和S分别），与P450 17A1的结合速度相对较慢。我们考虑了该药物是一种缓慢，紧密结合的抑制剂的可能性。结合动力学的分析表明，可能在底物结合位点快速形成了初始络合物，然后逐渐改变了最终铁络合物的光谱。在另一种抑制剂三唑（S-seviteronel（VT-464），带有P450 17A1。动力学测试和建模表明，进一步改变铁复合形式的Orteronel-或Seviteronel-P450复合物并不是抑制酶的先决条件。因此，在P450
• 1,1-Diarylalkenes as anticancer agents: Dual inhibitors of tubulin polymerization and phosphodiesterase 4
  作者：Alexander L. Ruchelman、Hon-Wah Man、Roger Chen、Wei Liu、Ling Lu、Dorota Cedzik、Ling Zhang、Jim Leisten、Alice Collette、Rama Krishna Narla、Heather K. Raymon、George W. Muller

  DOI：10.1016/j.bmc.2011.08.068

  日期：2011.11

  A series of 1,1-diarylalkene derivatives were prepared to optimize the properties of CC-5079 (1), a dual inhibitor of tubulin polymerization and phosphodiesterase 4 (PDE4). By using the 3-ethoxy-4-methoxyphenyl PDE4 pharmacophore as one of the aromatic rings, a significant improvement in PDE4 inhibition was achieved. Compound 28 was identified as a dual inhibitor with potent PDE4 (IC(50) = 54 nM) and antitubulin activity (HCT-116 IC(50) = 34 nM and tubulin polymerization IC(50) similar to 1 mu M). While the nitrile group at the alkene terminus was generally required for potent antiproliferative activity, its replacement was tolerated if there was a hydroxyl or amino group on one of the aryl rings. Conveniently, this group could also serve as a handle for amino acid derivatization to improve the compounds' solubility. The glycinamide analog 45 showed significant efficacy in the HCT-116 xenograft model, with 64% inhibition of tumor growth upon dosing at 20 mg/kg qd. (C) 2011 Elsevier Ltd. All rights reserved.