2′-(tert-butyl)-1-(1H-indazole-5-carbonyl)-2′H-spiro-[piperidine-4,5′-pyrano[3,2-c]pyrazol]-7′(6′H)-one | 1197815-64-7

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 哌啶类
• 英文名称: 2′-(tert-butyl)-1-(1H-indazole-5-carbonyl)-2′H-spiro-[piperidine-4,5′-pyrano[3,2-c]pyrazol]-7′(6′H)-one
• 英文别名: 2'-(tert-butyl)-1-(1H-indazole-5-carbonyl)-2'H-spiro[piperidine-4,5'-pyrano[3,2-c]pyrazol]-7'(6'H)-one；2'-tert-butyl-1-(1H-indazol-5-ylcarbonyl)-2'H-spiro[piperidine-4,5'-pyrano[3,2-c]pyrazol]-7'(6'H)-one；2'-Tert-Butyl-1-(2h-Indazol-5-Ylcarbonyl)-2'h-Spiro[piperidine-4,5'-Pyrano[3,2-C]pyrazol]-7'(6'h)-One；2-tert-butyl-1'-(1H-indazole-5-carbonyl)spiro[6H-pyrano[3,2-c]pyrazole-5,4'-piperidine]-7-one
• CAS: 1197815-64-7
• 化学式: C₂₂H₂₅N₅O₃
• 分子量: 407.472
• InChiKey: MDLAYXJCVDNKAB-UHFFFAOYSA-N

物化性质

• 沸点：
  669.2±55.0 °C(Predicted)
• 密度：
  1.41±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.1
• 重原子数：
  30
• 可旋转键数：
  2
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.45
• 拓扑面积：
  93.1
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  2′-(tert-butyl)-1-(1H-indazole-5-carbonyl)-2′H-spiro-[piperidine-4,5′-pyrano[3,2-c]pyrazol]-7′(6′H)-one 在 sodium tetrahydroborate 作用下， 以 甲醇 为溶剂， 反应 1.0h， 以67%的产率得到6'-tert-butyl-1-[(1H-indazol-5-yl)carbonyl]-4',6'-dihydro-3'H-spiro[piperidine-4,2'-pyrano[3,2-c]pyrazole]-4'-ol
  参考文献：
  名称：

  在临床乙酰辅酶A羧化酶抑制剂治疗糖尿病的发现中降低代谢酮还原的速率

  摘要：

  乙酰辅酶A羧化酶（ACC）抑制剂为2型糖尿病（T2DM），肝脂肪变性和癌症的治疗提供了巨大的潜力。然而，鉴定适于在人体试验中测试该假设的工具化合物一直具有挑战性。辉瑞公司最近报道的一系列先进的含螺环酮的ACC抑制剂在体内通过酮还原代谢，这使人的药理学预测复杂化。我们公开了通过与酮羰基相邻引入空间位阻，可以大大减轻这种代谢减少。弱碱性功能的引入改善了溶解度并导致鉴定出9作为治疗T2DM的临床候选药物。I期临床研究表明，暴露量与剂量成比例增加，新生脂肪生成（DNL）的单剂量抑制作用以及间接量热法的变化与全身脂肪酸氧化增加一致。靶标参与的这一证明验证了化合物9在评估DNL在人类疾病中的作用的使用。

  DOI：

  10.1021/jm5016022
• 作为产物：
  描述：

  2'-(叔丁基)-7'-氧代-6',7'-二氢-2'H-螺[哌啶-4,5'-吡喃并[3,2-C]吡唑]-1-甲酸 在 N-甲基吗啉 、 盐酸 、 2-氯-4,6-二甲氧基-1,3,5-三嗪 作用下， 以 1,4-二氧六环 为溶剂， 反应 6.5h， 生成 2′-(tert-butyl)-1-(1H-indazole-5-carbonyl)-2′H-spiro-[piperidine-4,5′-pyrano[3,2-c]pyrazol]-7′(6′H)-one
  参考文献：
  名称：

  Maximizing Lipophilic Efficiency: The Use of Free-Wilson Analysis in the Design of Inhibitors of Acetyl-CoA Carboxylase

  摘要：

  This paper describes the design and synthesis of a novel series of dual inhibitors of acetyl-CoA carboxylase 1 and 2 (ACC1 and ACC2). Key findings include the discovery of an initial lead that was modestly potent and subsequent medicinal chemistry optimization with a focus on lipophilic efficiency (LipE) to balance overall druglike properties. Free-Wilson methodology provided a clear breakdown of the contributions of specific structural elements to the overall LipE, a rationale for prioritization of virtual compounds for synthesis, and a highly successful prediction of the LipE of the resulting analogues. Further preclinical assays, including in vivo malonyl-CoA reduction in both rat liver (ACC1) and rat muscle (ACC2), identified an advanced analogue that progressed to regulatory toxicity studies.

  DOI：

  10.1021/jm201503u

文献信息

• [EN] USE OF ACETYL-COA CARBOXYLASE INHIBITORS FOR TREATING ACNE VULGARIS<br/>[FR] UTILISATION D'INHIBITEURS DE L'ACÉTYL-COA CARBOXYLASE POUR TRAITER L'ACNÉ VULGAIRE
  申请人：PFIZER

  公开号：WO2015036892A1

  公开（公告）日：2015-03-19

  The present invention relates to methods of treating and/or preventing acne in patients comprising the step of administering to patients in need of such treatment a therapeutically effective amount of an ACC inhibitor or a pharmaceutically acceptable salt thereof.

  本发明涉及治疗和/或预防痤疮的方法，包括向需要此类治疗的患者施用治疗有效量的ACC抑制剂或其药用盐。
• USE OF ACETYL-COA CARBOXYLASE INHIBITORS FOR TREATING ACNE VULGARIS
  申请人：PFIZER INC.

  公开号：US20160220557A1

  公开（公告）日：2016-08-04

  The present invention relates to methods of treating and/or preventing acne in patients comprising the step of administering to patients in need of such treatment a therapeutically effective amount of an ACC inhibitor or a pharmaceutically acceptable salt thereof.

  本发明涉及一种治疗和/或预防痤疮的方法，包括向需要此类治疗的患者施用治疗有效量的ACC抑制剂或其药学上可接受的盐。
• Pyrazolospiroketone Acetyl-Coa Carboxylase Inhibitors
  申请人：Freeman-Cook Kevin Daniel

  公开号：US20110009443A1

  公开（公告）日：2011-01-13

  The invention provides compounds of Formula (1) or a pharmaceutically acceptable salt of said compound, wherein R 1 , R 2 , and R 3 are as described herein; pharmaceutical compositions thereof; and the use thereof in treating mammals suffering from the condition of being overweight.

  本发明提供了式（1）的化合物或其药学上可接受的盐，其中R1、R2和R3如本文所述；其制备的药物组合物；以及用于治疗患有超重症的哺乳动物的用途。
• COMPOSITIONS AND METHODS TO TREAT NON-ALCOHOLIC FATTY LIVER DISEASES (NAFLD)
  申请人：Coherus Biosciences, Inc.

  公开号：US20220175758A1

  公开（公告）日：2022-06-09

  Provided herein are methods and combination therapies useful for the treatment of non-alcoholic fatty liver diseases (NAFLD). In particular, provided herein are methods and combination therapies for treating NAFLD by administering a combination therapy comprising (a) the compound of Formula (I), or a pharmaceutically acceptable salt thereof, and (b) an additional therapeutic agent, or a pharmaceutically acceptable salt thereof. Also provided are pharmaceutical compositions and pharmaceutical combinations comprising the compound of Formula (I), or a pharmaceutically acceptable salt thereof, and an additional therapeutic agent, or a pharmaceutically acceptable salt thereof.
• Maximizing Lipophilic Efficiency: The Use of Free-Wilson Analysis in the Design of Inhibitors of Acetyl-CoA Carboxylase
  作者：Kevin D. Freeman-Cook、Paul Amor、Scott Bader、Leanne M. Buzon、Steven B. Coffey、Jeffrey W. Corbett、Kenneth J. Dirico、Shawn D. Doran、Richard L. Elliott、William Esler、Angel Guzman-Perez、Kevin E. Henegar、Janet A. Houser、Christopher S. Jones、Chris Limberakis、Katherine Loomis、Kirk McPherson、Sharad Murdande、Kendra L. Nelson、Dennis Phillion、Betsy S. Pierce、Wei Song、Eliot Sugarman、Susan Tapley、Meihua Tu、Zhengrong Zhao

  DOI：10.1021/jm201503u

  日期：2012.1.26

  This paper describes the design and synthesis of a novel series of dual inhibitors of acetyl-CoA carboxylase 1 and 2 (ACC1 and ACC2). Key findings include the discovery of an initial lead that was modestly potent and subsequent medicinal chemistry optimization with a focus on lipophilic efficiency (LipE) to balance overall druglike properties. Free-Wilson methodology provided a clear breakdown of the contributions of specific structural elements to the overall LipE, a rationale for prioritization of virtual compounds for synthesis, and a highly successful prediction of the LipE of the resulting analogues. Further preclinical assays, including in vivo malonyl-CoA reduction in both rat liver (ACC1) and rat muscle (ACC2), identified an advanced analogue that progressed to regulatory toxicity studies.