(2-{(R)-3-[(6R,12aR)-6-(3,4-dimethoxyphenyl)-1,4-dioxo-3,6,7,12,12a-hexahydropyrazino[1',2':1,6]pyrido[3,4-b]indol-2-yl]pyrrolidin-1-yl}ethyl)carbamic acid tert-butyl ester | 1356345-70-4

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吲哚及其衍生物
• 英文名称: (2-{(R)-3-[(6R,12aR)-6-(3,4-dimethoxyphenyl)-1,4-dioxo-3,6,7,12,12a-hexahydropyrazino[1',2':1,6]pyrido[3,4-b]indol-2-yl]pyrrolidin-1-yl}ethyl)carbamic acid tert-butyl ester
• 英文别名: tert-butyl N-[2-[(3R)-3-[(2R,8R)-2-(3,4-dimethoxyphenyl)-4,7-dioxo-3,6,17-triazatetracyclo[8.7.0.03,8.011,16]heptadeca-1(10),11,13,15-tetraen-6-yl]pyrrolidin-1-yl]ethyl]carbamate
• CAS: 1356345-70-4
• 化学式: C₃₃H₄₁N₅O₆
• 分子量: 603.718
• InChiKey: PJDAELFJPWFTQG-WIISGGPLSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.4
• 重原子数：
  44
• 可旋转键数：
  9
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.48
• 拓扑面积：
  116
• 氢给体数：
  2
• 氢受体数：
  7

反应信息

• 作为产物：
  描述：

  (+/-) cis-methyl 1-(3,4-dimethoxyphenyl)-2,3,4,9-tetrahydro-1H-β-carboline-3-carboxylate 在 三乙胺 作用下， 以 1,4-二氧六环 、 甲醇 、 二氯甲烷 、 氯仿 为溶剂， 反应 21.0h， 生成 (2-{(R)-3-[(6R,12aR)-6-(3,4-dimethoxyphenyl)-1,4-dioxo-3,6,7,12,12a-hexahydropyrazino[1',2':1,6]pyrido[3,4-b]indol-2-yl]pyrrolidin-1-yl}ethyl)carbamic acid tert-butyl ester
  参考文献：
  名称：

  Drug-to-Genome-to-Drug, Step 2: Reversing Selectivity in a Series of Antiplasmodial Compounds

  摘要：

  In a recent paper, we have described the discovery of antimalarial compounds derived from tadalafil, using a drug-to-genome-to-drug approach (J. Med. Chem. 2011, 54 (9), pp 3222-3240). We have shown that these derivatives inhibit the phosphodiesterase activity of Plasmodium falciparum and the parasite growth in culture. In this paper, we describe the optimization of these compounds. A direct consequence of our approach based on gene orthology is the lack of selectivity of the compounds over the original activity on the human target. We demonstrate here that it is possible to take advantage of subtle differences in SAR between HsPDE5 inhibition and antiplasmodial activity to improve significantly the selectivity. In particular, the replacement of the piperonyl group in compound 2 by a dimethozyphenyl group was the best way to optimize selectivity. This observation is consistent with the differences between human and plasmodial sequences in the Q2 pocket receiving this group.

  DOI：

  10.1021/jm201422e