(4S)-5-[2-[(2S,3R)-1-[(2S)-1-[(2S,3R)-1-[(2S)-1-[(2S)-1-[(2S)-1-[(2S)-1-[(2S)-6-amino-1-[(2S)-1-[(2S)-1-[(2S)-1-[(2S)-1-[(2S)-1-[(2S)-1-[(2S)-1-[(2S)-1-[(2S)-1-[(2S)-1-[(2S,3S)-1-[(2S)-1-[(2S)-1-[(2S)-1-[(2S)-6-amino-1-[(2S)-1-[2-[2-[(2S)-2-[N-[(2S)-1-[(2S)-1-[2-[(2S)-1-[(2S)-2-[(2S)-2-[N-[(2S)-1-[(2S)-6-amino-1-[(2S)-6-amino-1-[(2S)-6-amino-1-[(2S)-6-amino-1-[(2S)-6-amino-1-[(2S)-6-amino-1-hydroxy-1-iminohexan-2-yl]imino-1-hydroxyhexan-2-yl]imino-1-hydroxyhexan-2-yl]imino-1-hydroxyhexan-2-yl]imino-1-hydroxyhexan-2-yl]imino-1-hydroxyhexan-2-yl]imino-1,3-dihydroxypropan-2-yl]-C-hydroxycarbonimidoyl]pyrrolidine-1-carbonyl]pyrrolidin-1-yl]-1-oxopropan-2-yl]imino-2-hydroxyethyl]imino-1,3-dihydroxypropan-2-yl]imino-1,3-dihydroxypropan-2-yl]-C-hydroxycarbonimidoyl]pyrrolidin-1-yl]-2-oxoethyl]imino-2-hydroxyethyl]imino-1,4-dihydroxy-4-iminobutan-2-yl]imino-1-hydroxyhexan-2-yl]imino-1-hydroxy-4-methylpentan-2-yl]imino-1-hydroxy-3-(1H-indol-3-yl)propan-2-yl]imino-4-carboxy-1-hydroxybutan-2-yl]imino-1-hydroxy-3-methylpentan-2-yl]imino-1-hydroxy-3-phenylpropan-2-yl]imino-1-hydroxy-4-methylpentan-2-yl]imino-5-carbamimidamido-1-hydroxypentan-2-yl]imino-1-hydroxy-3-methylbutan-2-yl]imino-1-hydroxypropan-2-yl]imino-4-carboxy-1-hydroxybutan-2-yl]imino-4-carboxy-1-hydroxybutan-2-yl]imino-4-carboxy-1-hydroxybutan-2-yl]imino-1-hydroxy-4-methylsulfanylbutan-2-yl]imino-1,5-dihydroxy-5-iminopentan-2-yl]imino-1-hydroxyhexan-2-yl]imino-1,3-dihydroxypropan-2-yl]imino-1-hydroxy-4-methylpentan-2-yl]imino-3-carboxy-1-hydroxypropan-2-yl]imino-1,3-dihydroxypropan-2-yl]imino-1,3-dihydroxybutan-2-yl]imino-1-hydroxy-3-phenylpropan-2-yl]imino-1,3-dihydroxybutan-2-yl]imino-2-hydroxyethyl]imino-4-[[2-[[(2S)-2-amino-1-hydroxy-3-(1H-imidazol-5-yl)propylidene]amino]-1-hydroxyethylidene]amino]-5-hydroxypentanoic acid

• 分子结构分类: 有机化合物 - 有机聚合物 - 多肽
• 英文名称: (4S)-5-[2-[(2S,3R)-1-[(2S)-1-[(2S,3R)-1-[(2S)-1-[(2S)-1-[(2S)-1-[(2S)-1-[(2S)-6-amino-1-[(2S)-1-[(2S)-1-[(2S)-1-[(2S)-1-[(2S)-1-[(2S)-1-[(2S)-1-[(2S)-1-[(2S)-1-[(2S)-1-[(2S,3S)-1-[(2S)-1-[(2S)-1-[(2S)-1-[(2S)-6-amino-1-[(2S)-1-[2-[2-[(2S)-2-[N-[(2S)-1-[(2S)-1-[2-[(2S)-1-[(2S)-2-[(2S)-2-[N-[(2S)-1-[(2S)-6-amino-1-[(2S)-6-amino-1-[(2S)-6-amino-1-[(2S)-6-amino-1-[(2S)-6-amino-1-[(2S)-6-amino-1-hydroxy-1-iminohexan-2-yl]imino-1-hydroxyhexan-2-yl]imino-1-hydroxyhexan-2-yl]imino-1-hydroxyhexan-2-yl]imino-1-hydroxyhexan-2-yl]imino-1-hydroxyhexan-2-yl]imino-1,3-dihydroxypropan-2-yl]-C-hydroxycarbonimidoyl]pyrrolidine-1-carbonyl]pyrrolidin-1-yl]-1-oxopropan-2-yl]imino-2-hydroxyethyl]imino-1,3-dihydroxypropan-2-yl]imino-1,3-dihydroxypropan-2-yl]-C-hydroxycarbonimidoyl]pyrrolidin-1-yl]-2-oxoethyl]imino-2-hydroxyethyl]imino-1,4-dihydroxy-4-iminobutan-2-yl]imino-1-hydroxyhexan-2-yl]imino-1-hydroxy-4-methylpentan-2-yl]imino-1-hydroxy-3-(1H-indol-3-yl)propan-2-yl]imino-4-carboxy-1-hydroxybutan-2-yl]imino-1-hydroxy-3-methylpentan-2-yl]imino-1-hydroxy-3-phenylpropan-2-yl]imino-1-hydroxy-4-methylpentan-2-yl]imino-5-carbamimidamido-1-hydroxypentan-2-yl]imino-1-hydroxy-3-methylbutan-2-yl]imino-1-hydroxypropan-2-yl]imino-4-carboxy-1-hydroxybutan-2-yl]imino-4-carboxy-1-hydroxybutan-2-yl]imino-4-carboxy-1-hydroxybutan-2-yl]imino-1-hydroxy-4-methylsulfanylbutan-2-yl]imino-1,5-dihydroxy-5-iminopentan-2-yl]imino-1-hydroxyhexan-2-yl]imino-1,3-dihydroxypropan-2-yl]imino-1-hydroxy-4-methylpentan-2-yl]imino-3-carboxy-1-hydroxypropan-2-yl]imino-1,3-dihydroxypropan-2-yl]imino-1,3-dihydroxybutan-2-yl]imino-1-hydroxy-3-phenylpropan-2-yl]imino-1,3-dihydroxybutan-2-yl]imino-2-hydroxyethyl]imino-4-[[2-[[(2S)-2-amino-1-hydroxy-3-(1H-imidazol-5-yl)propylidene]amino]-1-hydroxyethylidene]amino]-5-hydroxypentanoic acid
• 化学式: C₂₁₅H₃₄₇N₆₁O₆₅S
• 分子量: 4858.0
• InChiKey: XVVOERDUTLJJHN-IAEQDCLQSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -30.8
• 重原子数：
  342
• 可旋转键数：
  170
• 环数：
  8.0
• sp3杂化的碳原子比例：
  0.65
• 拓扑面积：
  2090
• 氢给体数：
  70
• 氢受体数：
  77

ADMET

毒理性

• 肝毒性

在大规模临床试验中，利西那肽治疗引起的血清酶升高并不比安慰剂或比较剂更常见。在对超过5000名患者的综合安全性分析中，ALT（谷丙转氨酶）升高超过正常上限3倍的情况在利西那肽组和安慰剂组中均发生了0.6%，并且没有报告与治疗相关的临床上明显的肝损伤案例。自从获得许可以来，没有发表过因利西那肽导致肝毒性的病例报告，而且产品标签上并未列出肝损伤作为不良反应。因此，如果利西那肽确实引起肝损伤，那么这种情况像其他GLP-1（胰高血糖素样肽-1）类似物一样，一定是罕见的，甚至可能根本不会发生。

In large clinical trials, serum enzyme elevations were no more common with lixisenatide therapy than with placebo or comparator agents. In pooled safety analyses of more than 5000 patients, ALT elevations above 3 times the upper limit of normal occurred in 0.6% of both lixisenatide and placebo groups and no instances of treatment related clinically apparent liver injury were reported. Since licensure, there have been no published case reports of hepatotoxicity due to lixisenatide and the product label does not list liver injury as an adverse event. Thus, liver injury due to lixisenatide, as with other GLP-1 analogues, must be rare, if it occurs at all.

来源:LiverTox