4-[(5R)-5-hydroxy-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-3-methylbenzonitrile

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡咯并吡唑类
• 英文名称: 4-[(5R)-5-hydroxy-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-3-methylbenzonitrile
• 英文别名: (R)-4-(5-hydroxy-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-3-methylbenzonitrile
• 化学式: C₁₄H₁₃N₃O
• 分子量: 239.277
• InChiKey: AJCNEVLJSPWGPZ-LLVKDONJSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.3
• 重原子数：
  18
• 可旋转键数：
  1
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.29
• 拓扑面积：
  61.8
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  4-[(5R)-5-hydroxy-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-3-methylbenzonitrile 在 戴斯-马丁氧化剂 作用下， 以 氯仿 为溶剂， 反应 4.0h， 以73%的产率得到3-methyl-4-(5-oxo-4,6-dihydropyrrolo[1,2-b]pyrazol-3-yl)benzonitrile
  参考文献：
  名称：

  Discovery of Novel Pyrazole-Based Selective Aldosterone Synthase (CYP11B2) Inhibitors: A New Template to Coordinate the Heme-Iron Motif of CYP11B2

  摘要：

  It is necessary for aldosterone synthase (CYP11B2) inhibitors to have both high potency and high selectivity over 11 beta-hydroxylase (CYP11B1), a critical enzyme for cortisol synthesis. Previous studies have reported a number of CYP11B2 inhibitors, most of which have an imidazole or pyridine ring to coordinate the heme-iron motif of CYP11B2; however, highly selective inhibitors of human CYP11B2 are still needed. To expand the selectivity in humans, we explored alternative templates and found that pyrazoles were suitable templates for CYP11B2 inhibitors. Investigation of pyrazoles, especially N-alkyl pyrazoles, as a new template to coordinate the hemeiron motif led to a potent and highly selective CYP11B2 inhibitor 28 with an aldosterone-lowering effect at 1 mg/kg dosing in cynomolgus monkeys.

  DOI：

  10.1021/acs.jmedchem.8b00328
• 作为产物：
  描述：

  [(5R)-5-benzyloxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl]trimethylsilane 在 bis-triphenylphosphine-palladium(II) chloride 、 10 wt% Pd(OH)2 on carbon 、 四丁基氟化铵 、 氢气 、 sodium carbonate 作用下， 以 四氢呋喃 、 乙二醇二甲醚 、 乙醇 、 水 为溶剂， 反应 48.0h， 生成 4-[(5R)-5-hydroxy-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-3-methylbenzonitrile
  参考文献：
  名称：

  Discovery of Novel Pyrazole-Based Selective Aldosterone Synthase (CYP11B2) Inhibitors: A New Template to Coordinate the Heme-Iron Motif of CYP11B2

  摘要：

  It is necessary for aldosterone synthase (CYP11B2) inhibitors to have both high potency and high selectivity over 11 beta-hydroxylase (CYP11B1), a critical enzyme for cortisol synthesis. Previous studies have reported a number of CYP11B2 inhibitors, most of which have an imidazole or pyridine ring to coordinate the heme-iron motif of CYP11B2; however, highly selective inhibitors of human CYP11B2 are still needed. To expand the selectivity in humans, we explored alternative templates and found that pyrazoles were suitable templates for CYP11B2 inhibitors. Investigation of pyrazoles, especially N-alkyl pyrazoles, as a new template to coordinate the hemeiron motif led to a potent and highly selective CYP11B2 inhibitor 28 with an aldosterone-lowering effect at 1 mg/kg dosing in cynomolgus monkeys.

  DOI：

  10.1021/acs.jmedchem.8b00328

文献信息

• [EN] NOVEL NITROGEN-CONTAINING HETEROCYCLIC COMPOUND<br/>[FR] NOUVEAU COMPOSÉ HÉTÉROCYCLIQUE CONTENANT DE L'AZOTE<br/>[JA] 新規含窒素複素環化合物
  申请人：MITSUBISHI TANABE PHARMA CORP

  公开号：WO2017170765A1

  公开（公告）日：2017-10-05

  本発明は、アルドステロン合成酵素の阻害活性を有し、アルドステロンが関与する各種疾患又は症状の予防、治療及び／又は予後改善に有用である、新規含窒素複素環化合物またはその薬理的に許容し得る塩、その製造方法、その使用、並びに前記化合物またはその薬理的に許容し得る塩を有効成分としてなる医薬組成物等を提供する。具体的には、本発明は、一般式（Ｉ）： 〔式中、記号は明細書に記載の意味を有する。〕 で示される化合物またはその薬理的に許容し得る塩、その製造方法、その使用、並びに前記化合物またはその薬理的に許容し得る塩を有効成分としてなる医薬組成物等を提供する。
• Discovery of Novel Pyrazole-Based Selective Aldosterone Synthase (CYP11B2) Inhibitors: A New Template to Coordinate the Heme-Iron Motif of CYP11B2
  作者：Ryo Sakakibara、Wataru Sasaki、Yuichi Onda、Minami Yamaguchi、Hideki Ushirogochi、Yuki Hiraga、Kanako Sato、Masashi Nishio、Yasuhiro Egi、Kei Takedomi、Hidetoshi Shimizu、Tomoko Ohbora、Fumihiko Akahoshi

  DOI：10.1021/acs.jmedchem.8b00328

  日期：2018.7.12

  It is necessary for aldosterone synthase (CYP11B2) inhibitors to have both high potency and high selectivity over 11 beta-hydroxylase (CYP11B1), a critical enzyme for cortisol synthesis. Previous studies have reported a number of CYP11B2 inhibitors, most of which have an imidazole or pyridine ring to coordinate the heme-iron motif of CYP11B2; however, highly selective inhibitors of human CYP11B2 are still needed. To expand the selectivity in humans, we explored alternative templates and found that pyrazoles were suitable templates for CYP11B2 inhibitors. Investigation of pyrazoles, especially N-alkyl pyrazoles, as a new template to coordinate the hemeiron motif led to a potent and highly selective CYP11B2 inhibitor 28 with an aldosterone-lowering effect at 1 mg/kg dosing in cynomolgus monkeys.