8-(4-Tert-butylbenzoyl)-3-(2-(4-(hydroxymethyl)piperidin-1-yl)-2-oxoethyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one | 1260000-91-6

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: 8-(4-Tert-butylbenzoyl)-3-(2-(4-(hydroxymethyl)piperidin-1-yl)-2-oxoethyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one
• 英文别名: 8-(4-tert-butylbenzoyl)-3-[2-[4-(hydroxymethyl)piperidin-1-yl]-2-oxoethyl]-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one
• CAS: 1260000-91-6
• 化学式: C₃₂H₄₂N₄O₄
• 分子量: 546.71
• InChiKey: HKEVZDBLHBQADG-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.2
• 重原子数：
  40
• 可旋转键数：
  6
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.53
• 拓扑面积：
  84.4
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  4-哌啶甲醇 、 2-(8-(4-(tert-butyl)benzoyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)acetic acid 在 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 N,N-二异丙基乙胺 作用下， 以 二氯甲烷 为溶剂， 反应 16.0h， 生成 8-(4-Tert-butylbenzoyl)-3-(2-(4-(hydroxymethyl)piperidin-1-yl)-2-oxoethyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one
  参考文献：
  名称：

  Spiroimidazolidinone NPC1L1 inhibitors. Part 2: Structure–activity studies and in vivo efficacy

  摘要：

  Ezetimibe (Zetia (R)), a cholesterol-absorption inhibitor (CAI) approved by the FDA for the treatment of hypercholesterolemia, is believed to target the intestine protein Niemann-Pick C1-Like 1 (NPC1L1) or its pathway. A spiroimidazolidinone NPC1L1 inhibitor identified by virtual screening showed moderate binding activity but was not efficacious in an in vivo rodent model of cholesterol absorption. Synthesis of analogs established the structure-activity relationships for binding activity, and resulted in compounds with in vivo efficacy, including 24, which inhibited plasma cholesterol absorption by 67% in the mouse, thereby providing proof-of-concept that non-beta-lactams can be effective CAIs. (C) 2010 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2010.09.138

文献信息

• Spiroimidazolidinone NPC1L1 inhibitors. Part 2: Structure–activity studies and in vivo efficacy
  作者：Kobporn L. Howell、Robert J. DeVita、Margarita Garcia-Calvo、Roger D. Meurer、JeanMarie Lisnock、Herbert G. Bull、Daniel R. McMasters、Margaret E. McCann、Sander G. Mills

  DOI：10.1016/j.bmcl.2010.09.138

  日期：2010.12

  Ezetimibe (Zetia (R)), a cholesterol-absorption inhibitor (CAI) approved by the FDA for the treatment of hypercholesterolemia, is believed to target the intestine protein Niemann-Pick C1-Like 1 (NPC1L1) or its pathway. A spiroimidazolidinone NPC1L1 inhibitor identified by virtual screening showed moderate binding activity but was not efficacious in an in vivo rodent model of cholesterol absorption. Synthesis of analogs established the structure-activity relationships for binding activity, and resulted in compounds with in vivo efficacy, including 24, which inhibited plasma cholesterol absorption by 67% in the mouse, thereby providing proof-of-concept that non-beta-lactams can be effective CAIs. (C) 2010 Elsevier Ltd. All rights reserved.