(S)-6-(7-fluoro-3-isobutyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-4-carbonyl)-2H-benzo[b]-[1,4]oxazin-3(4H)-one

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并恶嗪类
• 英文名称: (S)-6-(7-fluoro-3-isobutyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-4-carbonyl)-2H-benzo[b]-[1,4]oxazin-3(4H)-one
• 英文别名: 6-[[(3~{S})-7-fluoranyl-3-(2-methylpropyl)-2,3-dihydro-1,4-benzoxazin-4-yl]carbonyl]-4~{H}-1,4-benzoxazin-3-one；6-[(3S)-7-fluoro-3-(2-methylpropyl)-2,3-dihydro-1,4-benzoxazine-4-carbonyl]-4H-1,4-benzoxazin-3-one
• 化学式: C₂₁H₂₁FN₂O₄
• 分子量: 384.407
• InChiKey: CERMKIOTMWNAGM-HNNXBMFYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.5
• 重原子数：
  28
• 可旋转键数：
  3
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  67.9
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  1-bromo-4-methyl-2-pentanone 在 palladium 10% on activated carbon 、 氢气 、 potassium carbonate 、 1-丙基磷酸酐 、 三乙胺 作用下， 以 四氢呋喃 、 乙醇 、 溶剂黄146 、 乙酸乙酯 、 N,N-二甲基甲酰胺 为溶剂， 20.0~70.0 ℃ 、15.0 MPa 条件下， 反应 2.0h， 生成 (S)-6-(7-fluoro-3-isobutyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-4-carbonyl)-2H-benzo[b]-[1,4]oxazin-3(4H)-one
  参考文献：
  名称：

  Identification of Mineralocorticoid Receptor Modulators with Low Impact on Electrolyte Homeostasis but Maintained Organ Protection

  摘要：

  The mechanism-based risk for hyperkalemia has limited the use of mineralocorticoid receptor antagonists (MRAs) like eplerenone in cardio-renal diseases. Here, we describe the structure and property-driven lead generation and optimization, which resulted in identification of MR modulators (S)-1 and (S)-33. Both compounds were partial MRAs but still demonstrated equally efficacious organ protection as eplerenone after 4 weeks of treatment in uni-nephrectomized rats on high-salt diet and aldosterone infusion. Importantly, and in sharp contrast to eplerenone, this was achieved without substantial changes to the urine Na+/K+ ratio after acute treatment in rat, which predicts a reduced risk for hyperkalemia. This work led to selection of (S)-1 (AZD9977) as the clinical candidate for treating MR-mediated cardio-renal diseases, including chronic kidney disease and heart failure. On the basis of our findings, we propose an empirical model for prediction of compounds with low risk of affecting the urinary Na+/K+ ratio in vivo.

  DOI：

  10.1021/acs.jmedchem.8b01523

文献信息

• Identification of Mineralocorticoid Receptor Modulators with Low Impact on Electrolyte Homeostasis but Maintained Organ Protection
  作者：Kenneth L. Granberg、Zhong-Qing Yuan、Bo Lindmark、Karl Edman、Johan Kajanus、Anders Hogner、Marcus Malmgren、Gavin O’Mahony、Anneli Nordqvist、Jan Lindberg、Stefan Tångefjord、Michael Kossenjans、Christian Löfberg、Jonas Brånalt、Dongmei Liu、Nidhal Selmi、Grigorios Nikitidis、Peter Nordberg、Ahlke Hayen、Anna Aagaard、Eva Hansson、Majlis Hermansson、Ida Ivarsson、Rasmus Jansson-Löfmark、Ulla Karlsson、Ulrika Johansson、Lena William-Olsson、Judith Hartleib-Geschwindner、Krister Bamberg

  DOI：10.1021/acs.jmedchem.8b01523

  日期：2019.2.14

  The mechanism-based risk for hyperkalemia has limited the use of mineralocorticoid receptor antagonists (MRAs) like eplerenone in cardio-renal diseases. Here, we describe the structure and property-driven lead generation and optimization, which resulted in identification of MR modulators (S)-1 and (S)-33. Both compounds were partial MRAs but still demonstrated equally efficacious organ protection as eplerenone after 4 weeks of treatment in uni-nephrectomized rats on high-salt diet and aldosterone infusion. Importantly, and in sharp contrast to eplerenone, this was achieved without substantial changes to the urine Na+/K+ ratio after acute treatment in rat, which predicts a reduced risk for hyperkalemia. This work led to selection of (S)-1 (AZD9977) as the clinical candidate for treating MR-mediated cardio-renal diseases, including chronic kidney disease and heart failure. On the basis of our findings, we propose an empirical model for prediction of compounds with low risk of affecting the urinary Na+/K+ ratio in vivo.