(1R,3R)-1-tetrazolo[1,5-a]pyridin-6-yl-2,3,4,9-tetrahydro-1H-β-carboline-3-carboxylic acid methyl ester trifluoroacetate salt | 1356345-82-8

• 分子结构分类: 有机化合物 - 生物碱及其衍生物 - 哈马拉生物碱
• 英文名称: (1R,3R)-1-tetrazolo[1,5-a]pyridin-6-yl-2,3,4,9-tetrahydro-1H-β-carboline-3-carboxylic acid methyl ester trifluoroacetate salt
• CAS: 1356345-82-8
• 化学式: C₂HF₃O₂*C₁₈H₁₆N₆O₂
• 分子量: 462.388
• InChiKey: QLWWKDNEOTWNPE-VNYZMKMESA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.02
• 重原子数：
  33.0
• 可旋转键数：
  2.0
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.25
• 拓扑面积：
  134.5
• 氢给体数：
  3.0
• 氢受体数：
  8.0

反应信息

• 作为反应物：
  描述：

  (1R,3R)-1-tetrazolo[1,5-a]pyridin-6-yl-2,3,4,9-tetrahydro-1H-β-carboline-3-carboxylic acid methyl ester trifluoroacetate salt 在 三乙胺 作用下， 以 甲醇 、 氯仿 为溶剂， 生成 (6R,12aR)-2-((R)-1-benzylpyrrolidin-3-yl)-6-tetrazolo[1.5-a]-pyridin-6-yl-2,3,6,7,12,12a-hexahydropyrazino[1',2':1,6]pyrido[3,4-b]indole-1,4-dione
  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
• 作为产物：
  描述：

  2-氯-5-羟甲基吡啶 在 manganese(IV) oxide 、 sodium azide 作用下， 以 乙醇 、 二氯甲烷 、 氯仿 为溶剂， 生成 (1R,3R)-1-tetrazolo[1,5-a]pyridin-6-yl-2,3,4,9-tetrahydro-1H-β-carboline-3-carboxylic acid methyl ester trifluoroacetate salt 、 (1S,3R)-1-tetrazolo[1,5-a]pyridin-6-yl-2,3,4,9-tetrahydro-1H-β-carboline-3-carboxylic acid methyl ester trifluoroacetate salt
  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