SPL-707

• 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: SPL-707
• 英文别名: (2S)-2-cyclopropyl-N-[(6S)-5,11-dioxospiro[3,6-dihydro-1H-pyrazolo[1,2-b][2,3]benzodiazepine-2,1'-cyclopropane]-6-yl]-N'-(5-fluoro-2-methylpyridin-3-yl)butanediamide
• 化学式: C₂₇H₂₈FN₅O₄
• 分子量: 505.549
• InChiKey: WLQXBRYTQYYCMW-REWPJTCUSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.9
• 重原子数：
  37
• 可旋转键数：
  6
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.44
• 拓扑面积：
  112
• 氢给体数：
  2
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  环丙乙酸 在 吡啶 、 4-二甲氨基吡啶 、 双氧水 、 sodium hexamethyldisilazane 、 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 、 三氟乙酸 、 N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate 、 lithium hydroxide 作用下， 以 四氢呋喃 、 二氯甲烷 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 102.0h， 生成 SPL-707
  参考文献：
  名称：

  Discovery of the First Potent, Selective, and Orally Bioavailable Signal Peptide Peptidase-Like 2a (SPPL2a) Inhibitor Displaying Pronounced Immunomodulatory Effects In Vivo

  摘要：

  Signal peptide peptidase-like 2a (SPPL2a) is an aspartic intramembrane protease which has recently been shown to play an important role in the development and function of antigen presenting cells such as B lymphocytes and dendritic cells. In this paper, we describe the discovery of the first selective and orally active SPPL2a inhibitor (S)-2-cyclopropyl-N1-((S)-5,11-dioxo-10,11-dihydro-1H,3H,5H-spiro[benzo[d]pyrazolo[1,2-a][1,2]diazepine-2,1'-cyclopropan]-10-yl)-N4-(5-fluoro-2-methylpyridin-3-yl)succinamide 40 (SPL-707). This compound shows adequate selectivity against the closely related enzymes gamma-secretase and SPP and a good pharmacokinetic profile in mouse and rat. Compound 40 significantly inhibited processing of the SPPL2a substrate CD74/p8 fragment in rodents at doses <= 10 mg/kg b.i.d. po. Oral dosing of 40 for 11 days at >= 10 mg/kg b.i.d. recapitulated the phenotype seen in Sppl2a knockout (ko) and ENU mutant mice (reduced number of specific B cells and myeloid dendritic cells). Thus, we believe that SPPL2a represents an interesting and druggable pharmacological target, potentially providing a novel approach for the treatment of autoimmune diseases by targeting B cells and dendritic cells.

  DOI：

  10.1021/acs.jmedchem.7b01371