MDL 104168 | 158268-42-9

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 肽模拟物
• 英文名称: MDL 104168
• 英文别名: [9(S),12(S)]-α,α-Difluoro-9-(1-methylethyl)-β,4,7,10-tetraoxo-N-(phenylmethyl)-2-oxa-5,8,11,-triazabicyclo[12.2.2]octadeca-14,16,17-triene-12-propanamide；N-Benzyl-2,2-difluoro-3-((9S,12S)-9-isopropyl-4,7,10-trioxo-2-oxa-5,8,11-triaza-bicyclo[12.2.2]octadeca-1(17),14(18),15-trien-12-yl)-3-oxo-propionamide；N-benzyl-2,2-difluoro-3-oxo-3-[(9S,12S)-4,7,10-trioxo-9-propan-2-yl-2-oxa-5,8,11-triazabicyclo[12.2.2]octadeca-1(16),14,17-trien-12-yl]propanamide
• CAS: 158268-42-9
• 化学式: C₂₇H₃₀F₂N₄O₆
• 分子量: 544.555
• InChiKey: FENHLDPCCNRQQC-REWPJTCUSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.8
• 重原子数：
  39
• 可旋转键数：
  6
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.37
• 拓扑面积：
  143
• 氢给体数：
  4
• 氢受体数：
  8

反应信息

• 作为产物：
  描述：

  甘氨酰-L-缬氨酸 在 N-甲基吗啉 、 盐酸 、 lithium hydroxide 、 碳酸氢钠 、 戴斯-马丁氧化剂 、 1-(3-二甲基氨基丙基)-3-乙基碳二亚胺 、 1-羟基苯并三唑一水物 、 三乙胺 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 甲醇 、 氘代二甲亚砜 、 二氯甲烷 、 水 、 N,N-二甲基甲酰胺 、 乙腈 为溶剂， 反应 318.0h， 生成 MDL 104168
  参考文献：
  名称：

  Design, Synthesis, and Conformational Analysis of a Novel Macrocyclic HIV-Protease Inhibitor

  摘要：

  Design modifications to the lead HnT-PR inhibitor 1 (MDL 73,669, K-i = 5 nM) have been postulated based on a computational model of the 1/HIV-PR complex. A novel macrocyclic inhibitor 8 (MDL 104,168) wherein the P-1 and P-3 Side chains of the original acyclic inhibitor have been joined retains good biological activity (K-i = 20 nM). NMR analysis of the precursor alcohol (S)-7 shows the conformation of the cyclic region to be very similar to that observed in the enzyme-bound 8 as determined by the computational model. Consistency of the computational model with NMR data and in vacuo molecular dynamics simulations provide the basis for postulating further modifications of the cyclic inhibitor expected to optimize its interactions with HIV-PR.

  DOI：

  10.1021/jm00048a004

文献信息

• Macrocyclic difluorostatone derivatives useful as antiviral agents
  申请人：Merrell Pharmaceuticals Inc.

  公开号：US05969132A1

  公开（公告）日：1999-10-19

  The present invention provides novel macrocyclic difluorostatone derivatives which are useful as antiviral agents. More specifically, these novel compounds are useful as inhibitors of retroviral proteases required for replication, particularly the HIV-1 and HIV-2 viral proteases, in the prevention or treatment of infection by the human immunodeficiency virus (HIV), and in the treatment of consequent pathological conditions such as the acquired immunodeficiency syndrome (AIDS) in mammals capable of being infected with HIV virus.

  本发明提供了一种新型的巨环二氟基稳酮衍生物，可用作抗病毒药物。更具体地说，这些新型化合物可用作抑制逆转录病毒蛋白酶的药物，该蛋白酶在人类免疫缺陷病毒（HIV）感染的预防或治疗中起关键作用，特别是HIV-1和HIV-2病毒蛋白酶，以及在能够被HIV病毒感染的哺乳动物中治疗由此引起的病理状况，如获得性免疫缺陷综合症（AIDS）。
• Design, Synthesis, and Conformational Analysis of a Novel Macrocyclic HIV-Protease Inhibitor
  作者：Brent L. Podlogar、Robert A. Farr、Dirk Friedrich、Celine Tarnus、Edward W. Huber、Robert J. Cregge、Daniel Schirlin

  DOI：10.1021/jm00048a004

  日期：1994.10

  Design modifications to the lead HnT-PR inhibitor 1 (MDL 73,669, K-i = 5 nM) have been postulated based on a computational model of the 1/HIV-PR complex. A novel macrocyclic inhibitor 8 (MDL 104,168) wherein the P-1 and P-3 Side chains of the original acyclic inhibitor have been joined retains good biological activity (K-i = 20 nM). NMR analysis of the precursor alcohol (S)-7 shows the conformation of the cyclic region to be very similar to that observed in the enzyme-bound 8 as determined by the computational model. Consistency of the computational model with NMR data and in vacuo molecular dynamics simulations provide the basis for postulating further modifications of the cyclic inhibitor expected to optimize its interactions with HIV-PR.