(6aR,10aS)-10a-((4-chlorophenyl)sulfonyl)-1,4-difluoro-2′-methyl-6,6a,8,9,10,10a-hexahydrospiro[benzo[c]-chromene-7,5′-[1,3,2]dioxaphosphinane] 2′-oxide

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并吡喃
• 英文名称: (6aR,10aS)-10a-((4-chlorophenyl)sulfonyl)-1,4-difluoro-2′-methyl-6,6a,8,9,10,10a-hexahydrospiro[benzo[c]-chromene-7,5′-[1,3,2]dioxaphosphinane] 2′-oxide
• 英文别名: US9464103, (6'R,6aR,7r,10aS)-10a-(4-chlorobenzenesulfonyl)-1,4-difluoro-6'-methyl-6,6a,8,9,10,10a-hexahydrospiro[benzo[c]isochromene-7,3'-[1,5,6lambda�?�]dioxaphosphinane]-6'-one；(6'aR,10'aS)-10'a-(4-chlorophenyl)sulfonyl-1',4'-difluoro-2-methylspiro[1,3,2λ5-dioxaphosphinane-5,7'-6a,8,9,10-tetrahydro-6H-benzo[c]chromene] 2-oxide
• 化学式: C₂₂H₂₂ClF₂O₆PS
• 分子量: 518.903
• InChiKey: HYGZSKLILPYKMS-LZYVTZSCSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.3
• 重原子数：
  33
• 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：
  87.3
• 氢给体数：
  0
• 氢受体数：
  8

反应信息

• 作为产物：
  描述：

  烯丙基丙二酸二甲酯 在 吡啶 、 9-borabicyclo[3.3.1]nonane dimer 、 potassium tert-butylate 、 4-甲基苯磺酸吡啶 、 二异丁基氢化铝 、 potassium carbonate 、 溶剂黄146 、 三乙胺 作用下， 以 四氢呋喃 、 正己烷 、 二氯甲烷 、 水 为溶剂， 反应 30.58h， 生成 (6aR,10aS)-10a-((4-chlorophenyl)sulfonyl)-1,4-difluoro-2′-methyl-6,6a,8,9,10,10a-hexahydrospiro[benzo[c]-chromene-7,5′-[1,3,2]dioxaphosphinane] 2′-oxide
  参考文献：
  名称：

  Discovery of a Novel, Potent Spirocyclic Series of γ-Secretase Inhibitors

  摘要：

  In the present paper, we described the design, synthesis, SAR, and biological profile of a novel spirocyclic sulfone series of gamma-secretase inhibitors (GSIs) related to MRK-560. We utilized an additional spirocyclic ring system to stabilize the active chair conformation of the parent ?-secretase inhibitors. The resulting series is devoid of the CYP2C9 inhibition liability of MRK-560. A few representative analogs were assessed in a nontransgenic animal model of Alzheimer's disease (AD), demonstrating reduction of amyloid-? (A beta) in the CNS after acute oral dosing. A spirocyclic phosphonate was identified as the optimal ring system for both potency and pharmacokinetics. Compared to GSIs studied in the clinic, representative spirocyclic phosphonate 18a(-) features improved selectivity for the inhibition of the PS-1 isoform of ?-secretase (33-fold vs PS-2), which may alleviate the adverse effect profile of the clinical GSIs.

  DOI：

  10.1021/acs.jmedchem.5b00774

文献信息

• Discovery of a Novel, Potent Spirocyclic Series of γ-Secretase Inhibitors
  作者：Zhiqiang Zhao、Dmitri A. Pissarnitski、Hubert B. Josien、Wen-Lian Wu、Ruo Xu、Hongmei Li、John W. Clader、Duane A. Burnett、Giuseppe Terracina、Lynn Hyde、Julie Lee、Lixin Song、Lili Zhang、Eric M. Parker

  DOI：10.1021/acs.jmedchem.5b00774

  日期：2015.11.25

  In the present paper, we described the design, synthesis, SAR, and biological profile of a novel spirocyclic sulfone series of gamma-secretase inhibitors (GSIs) related to MRK-560. We utilized an additional spirocyclic ring system to stabilize the active chair conformation of the parent ?-secretase inhibitors. The resulting series is devoid of the CYP2C9 inhibition liability of MRK-560. A few representative analogs were assessed in a nontransgenic animal model of Alzheimer's disease (AD), demonstrating reduction of amyloid-? (A beta) in the CNS after acute oral dosing. A spirocyclic phosphonate was identified as the optimal ring system for both potency and pharmacokinetics. Compared to GSIs studied in the clinic, representative spirocyclic phosphonate 18a(-) features improved selectivity for the inhibition of the PS-1 isoform of ?-secretase (33-fold vs PS-2), which may alleviate the adverse effect profile of the clinical GSIs.