(1S,10S,21R)-7-ethylidene-4,21-di(propan-2-yl)-2-oxa-12,13-dithia-5,8,20,23-tetrazabicyclo[8.7.6]tricos-16-ene-3,6,9,19,22-pentone

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 肽模拟物
• 英文名称: (1S,10S,21R)-7-ethylidene-4,21-di(propan-2-yl)-2-oxa-12,13-dithia-5,8,20,23-tetrazabicyclo[8.7.6]tricos-16-ene-3,6,9,19,22-pentone
• 化学式: C₂₄H₃₆N₄O₆S₂
• 分子量: 540.7
• InChiKey: OHRURASPPZQGQM-MWQPNCDWSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.2
• 重原子数：
  36
• 可旋转键数：
  2
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.62
• 拓扑面积：
  193
• 氢给体数：
  4
• 氢受体数：
  8

ADMET

毒理性

• 肝毒性

在 romidepsin 治疗皮肤 T 细胞淋巴瘤 (CTLC) 和外周 T 细胞淋巴瘤 (PTLC) 的临床试验中，治疗期间血清酶水平升高的发生率在 7% 到 20% 之间，但这些异常通常是暂时的和轻微的，不需要调整剂量。血清 ALT 升高超过 5 倍正常上限 (ULN) 的患者占 6%。在 romidepsin 的预注册临床试验中，治疗对象中没有肝炎、黄疸或临床上明显的肝损伤的报告。Romidepsin 在临床上的使用有限，但没有证据表明它与严重的肝损伤有关。 Romidepsin 还具有免疫调节活性，并据报道可以引起潜伏 DNA 病毒的再激活，包括Epstein-Barr 病毒、水痘带状疱疹病毒和乙型肝炎病毒。在一项患者中，乙型肝炎的再激活发生在最初 HBsAg 阴性但抗-HBc 和抗-HBs 阳性的患者中。尽管如此，乙型肝炎再激活的临床特征是轻微的，并对口服抗病毒治疗有反应。在患有与EB病毒相关的淋巴瘤的患者中，romidepsin 与 EB 病毒感染的严重再激活和急性肝炎有关，这种肝炎可能很严重，甚至可能是致命的。 可能性评分：C（可能是临床上明显肝损伤的原因，可能是由乙型肝炎或 EB 病毒感染的再激活引起的）。

In clinical trials of romidepsin in patients with CTLC and PTLC, the rates of serum enzyme elevations during therapy ranged from 7% to 20%, but the abnormalities were usually transient and mild and did not require dose modifications. Serum ALT elevations above 5 times ULN occurred in 6% of patients. In the preregistration clinical trials of romidepsin, there were no reports of hepatitis, jaundice or clinically apparent liver injury among the treated subjects. Romidepsin has had limited clinical use, but there is no evidence that it is associated with significant liver injury. Romidepsin also has immunomodulatory activities and has been reported to cause reactivation of latent DNA viruses including Epstein-Barr, varicella zoster and hepatitis B virus. Reactivation of hepatitis B occurred in a patient who was initially negative for HBsAg, but reactive for anti-HBc and anti-HBs. Nevertheless, the clinical features of hepatitis B reactivation were mild and responded to oral antiviral therapy. In patients with EBV associated lymphoma, romidepsin has been associated with severe reactivation of EBV infection and acute hepatitis that can be severe and even fatal. Likelihood score: C (probable cause of clinically apparent liver injury, which can be due to reactivation of hepatitis B or EBV infection).

来源:LiverTox

文献信息

• FLOUROUS METABOLICALLY STABLE PEPTIDE ANALOGS
  申请人：Université de Strasbourg

  公开号：EP3257863A1

  公开（公告）日：2017-12-20

  The present invention relates to metabolically stable and non-immunogen analogs completely hydrosoluble at physiological pH, and their use for the prevention or treatment of diseases mediated by G-protein coupled receptor (GPCR), in particular (Central Nervous System) CNS and cardiovascular diseases or disorders.

  本发明涉及在生理 pH 值下完全水溶的代谢稳定的非免疫原类似物，以及它们在预防或治疗由 G 蛋白偶联受体（GPCR）介导的疾病，特别是（中枢神经系统）中枢神经系统和心血管疾病或紊乱方面的用途。