methyl (1R,2S)-1-[[(2S,4R)-1-[(2S)-2-(cyclopentyloxycarbonylamino)-3,3-dimethylbutanoyl]-4-[2-[2-(3,3-dimethylbutanoylamino)-1,3-thiazol-4-yl]-7-methoxyquinolin-4-yl]oxypyrrolidine-2-carbonyl]amino]-2-ethenylcyclopropane-1-carboxylate | 572924-06-2

• 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 (1R,2S)-1-[[(2S,4R)-1-[(2S)-2-(cyclopentyloxycarbonylamino)-3,3-dimethylbutanoyl]-4-[2-[2-(3,3-dimethylbutanoylamino)-1,3-thiazol-4-yl]-7-methoxyquinolin-4-yl]oxypyrrolidine-2-carbonyl]amino]-2-ethenylcyclopropane-1-carboxylate
• CAS: 572924-06-2
• 化学式: C₄₃H₅₆N₆O₉S
• 分子量: 833.018
• InChiKey: CJPBLOLBVQWEJL-TVPZQHORSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.7
• 重原子数：
  59
• 可旋转键数：
  17
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.56
• 拓扑面积：
  216
• 氢给体数：
  3
• 氢受体数：
  12

反应信息

• 作为反应物：
  描述：

  methyl (1R,2S)-1-[[(2S,4R)-1-[(2S)-2-(cyclopentyloxycarbonylamino)-3,3-dimethylbutanoyl]-4-[2-[2-(3,3-dimethylbutanoylamino)-1,3-thiazol-4-yl]-7-methoxyquinolin-4-yl]oxypyrrolidine-2-carbonyl]amino]-2-ethenylcyclopropane-1-carboxylate 在 lithium hydroxide monohydrate 、 水 作用下， 以 四氢呋喃 、 甲醇 为溶剂， 生成 N-[(cyclopentyloxy)carbonyl]-3-methyl-L-valyl-(4R)-N-[(1R,2S)-1-carboxy-2-ethenylcyclopropyl]-4-[(2-{2-[(3,3-dimethylbutanoyl)-amino]-1,3-thiazol-4-yl}-7-methoxyquinolin-4-yl)oxy]-L-prolinamide
  参考文献：
  名称：

  Discovery of a Potent and Selective Noncovalent Linear Inhibitor of the Hepatitis C Virus NS3 Protease (BI 201335)

  摘要：

  C-Terminal carboxylic acid containing inhibitors of the NS3 protease are reported. A novel series of linear tripeptide inhibitors that are very potent and selective against the NS3 protease are described. A substantial contribution to the potency of these linear inhibitors arises from the introduction of a C8 substituent on the B-ring of the quinoline moiety found on the P2 of these inhibitors. The introduction of a CS methyl group results not only in a modest increase in the cell-based potency of these inhibitors but more importantly in a much better pharmacokinetic profile in rats as well. Exploration of C8-substitutions led to the identification of the bromo derivative as the best group at this position, resulting in a significant increase in the cell-based potency of this class of inhibitors. Structure activity studies on the C8-bromo derivatives ultimately led to the discovery of clinical candidate 29 (BI 201335), a very potent and selective inhibitor of genotypel NS3 protease with a promising PK profile in rats.

  DOI：

  10.1021/jm100690x
• 作为产物：
  描述：

  N-carbamothioyl-3,3-dimethylbutanamide 、 methyl (1R,2S)-1-[[(2S,4R)-4-[2-(2-bromoacetyl)-7-methoxyquinolin-4-yl]oxy-1-[(2S)-2-(cyclopentyloxycarbonylamino)-3,3-dimethylbutanoyl]pyrrolidine-2-carbonyl]amino]-2-ethenylcyclopropane-1-carboxylate 以 异丙醇 为溶剂， 反应 1.0h， 生成 methyl (1R,2S)-1-[[(2S,4R)-1-[(2S)-2-(cyclopentyloxycarbonylamino)-3,3-dimethylbutanoyl]-4-[2-[2-(3,3-dimethylbutanoylamino)-1,3-thiazol-4-yl]-7-methoxyquinolin-4-yl]oxypyrrolidine-2-carbonyl]amino]-2-ethenylcyclopropane-1-carboxylate
  参考文献：
  名称：

  Discovery of a Potent and Selective Noncovalent Linear Inhibitor of the Hepatitis C Virus NS3 Protease (BI 201335)

  摘要：

  C-Terminal carboxylic acid containing inhibitors of the NS3 protease are reported. A novel series of linear tripeptide inhibitors that are very potent and selective against the NS3 protease are described. A substantial contribution to the potency of these linear inhibitors arises from the introduction of a C8 substituent on the B-ring of the quinoline moiety found on the P2 of these inhibitors. The introduction of a CS methyl group results not only in a modest increase in the cell-based potency of these inhibitors but more importantly in a much better pharmacokinetic profile in rats as well. Exploration of C8-substitutions led to the identification of the bromo derivative as the best group at this position, resulting in a significant increase in the cell-based potency of this class of inhibitors. Structure activity studies on the C8-bromo derivatives ultimately led to the discovery of clinical candidate 29 (BI 201335), a very potent and selective inhibitor of genotypel NS3 protease with a promising PK profile in rats.

  DOI：

  10.1021/jm100690x