methyl 3-(1-(2-(3,4-dimethoxyphenyl)-2-(1-methyl-3-oxoisoindolin-5-ylamino)acetyl)pyrrolidin-2-yl)-4-(isopropylsulfonyl)phenylcarbamate

• 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: methyl 3-(1-(2-(3,4-dimethoxyphenyl)-2-(1-methyl-3-oxoisoindolin-5-ylamino)acetyl)pyrrolidin-2-yl)-4-(isopropylsulfonyl)phenylcarbamate
• 英文别名: methyl N-[3-[1-[2-(3,4-dimethoxyphenyl)-2-[(1-methyl-3-oxo-1,2-dihydroisoindol-5-yl)amino]acetyl]pyrrolidin-2-yl]-4-propan-2-ylsulfonylphenyl]carbamate
• 化学式: C₃₄H₄₀N₄O₈S
• 分子量: 664.78
• InChiKey: LAUVCJWPBYKZPC-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4
• 重原子数：
  47
• 可旋转键数：
  11
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.38
• 拓扑面积：
  161
• 氢给体数：
  3
• 氢受体数：
  9

反应信息

• 作为产物：
  描述：

  2-乙酰苯甲酸 在 N-羟基-7-氮杂苯并三氮唑 、 硫酸 、 palladium 10% on activated carbon 、 palladium on activated charcoal 、 氢气 、 1-(3-二甲基氨基丙基)-3-乙基碳二亚胺 、 potassium nitrate 、 N,N-二异丙基乙胺 、 三氟乙酸 作用下， 以 甲醇 、 二氯甲烷 、 水 、 N,N-二甲基甲酰胺 、 甲苯 、 乙腈 为溶剂， 200.0 ℃ 、344.75 kPa 条件下， 反应 7.42h， 生成 methyl 3-(1-(2-(3,4-dimethoxyphenyl)-2-(1-methyl-3-oxoisoindolin-5-ylamino)acetyl)pyrrolidin-2-yl)-4-(isopropylsulfonyl)phenylcarbamate
  参考文献：
  名称：

  Discovery of Phenylglycine Lactams as Potent Neutral Factor VIIa Inhibitors

  摘要：

  Inhibitors of Factor Vila (FVIIa), a serine protease in the clotting cascade, have shown strong antithrombotic efficacy in preclinical thrombosis models with minimal bleeding liabilities. Discovery of potent, orally active FVIIa inhibitors has been largely unsuccessful because known chemotypes have required a highly basic group in the Si binding pocket for high affinity. A recently reported fragment screening effort resulted in the discovery of a neutral heterocycle, 7-chloro-3,4-dihydroisoquinolin-1(2H)-one, that binds in the Si pocket of FVIIa and can be incorporated into a phenylglycine FVIIa inhibitor. Optimization of this PI binding group led to the first series of neutral, permeable FVIIa inhibitors with low nanomolar potency.

  DOI：

  10.1021/acsmedchemlett.6b00282

文献信息

• Discovery of Phenylglycine Lactams as Potent Neutral Factor VIIa Inhibitors
  作者：Nicholas R. Wurtz、Brandon L. Parkhurst、Wen Jiang、Indawati DeLucca、Xiaojun Zhang、Vladimir Ladziata、Daniel L. Cheney、Jeffrey R. Bozarth、Alan R. Rendina、Anzhi Wei、Joseph M. Luettgen、Yiming Wu、Pancras C. Wong、Dietmar A. Seiffert、Ruth R. Wexler、E. Scott Priestley

  DOI：10.1021/acsmedchemlett.6b00282

  日期：2016.12.8

  Inhibitors of Factor Vila (FVIIa), a serine protease in the clotting cascade, have shown strong antithrombotic efficacy in preclinical thrombosis models with minimal bleeding liabilities. Discovery of potent, orally active FVIIa inhibitors has been largely unsuccessful because known chemotypes have required a highly basic group in the Si binding pocket for high affinity. A recently reported fragment screening effort resulted in the discovery of a neutral heterocycle, 7-chloro-3,4-dihydroisoquinolin-1(2H)-one, that binds in the Si pocket of FVIIa and can be incorporated into a phenylglycine FVIIa inhibitor. Optimization of this PI binding group led to the first series of neutral, permeable FVIIa inhibitors with low nanomolar potency.