珀奈莫德; | 854107-55-4

• 物质功能分类: 生物化工 - 生化试剂 - 激动剂抑制剂
• 分子结构分类: 有机化合物 - 苯类化合物 - 苯酚醚
• 中文名称: 珀奈莫德
• 中文别名: 鞘氨醇-1-磷酸受体1(S1P1)调节剂；珀奈莫德
• 英文名称: Ponesimod
• 英文别名: (5Z)-5-[[3-chloro-4-[(2R)-2,3-dihydroxypropoxy]phenyl]methylidene]-3-(2-methylphenyl)-2-propylimino-1,3-thiazolidin-4-one
• CAS: 854107-55-4
• 化学式: C₂₃H₂₅ClN₂O₄S
• 分子量: 461.0
• InChiKey: LPAUOXUZGSBGDU-ULCCENQXSA-N

物化性质

• 沸点：
  658.0±65.0 °C(Predicted)
• 密度：
  1.30±0.1 g/cm3(Predicted)
• 溶解度：
  溶于二甲基亚砜

计算性质

• 辛醇/水分配系数(LogP)：
  4.6
• 重原子数：
  31
• 可旋转键数：
  8
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.3
• 拓扑面积：
  108
• 氢给体数：
  2
• 氢受体数：
  6

ADMET

代谢

Ponesimod可被硫酸化成M5代谢物，氧化成未明确的M27代谢物，还原成M6代谢物，脱烷基成M32代谢物，或者氧化和水解成M13代谢物。Ponesimod还可以被CYP2J2、CYP3A4、CYP3A5、CYP4F3A和CYP4F12氧化成M12代谢物。未明确的M27代谢物可以被UGT1A1和UGT 2B7葡萄糖醛酸化成M38、M39和M40代谢物。M12代谢物要么脱烷基成M32代谢物，要么氧化和水解成M13。M13脱烷基成M32，M32再还原和氧化成M48。

Ponesimod can be sulfated to the M5 metabolite, oxidized to an undefined M27 metabolite, reduced to the M6 metabolite, dealkylated to the M32 metabolite, or oxidized and hydrolyzed to the M13 metabolite. Ponesimod can also be oxidized by CYP2J2, CYP3A4, CYP3A5, CYP4F3A, and CYP4F12 to the M12 metabolite. The undefined M27 metabolite can be glucuronidated by UGT1A1 and UGT 2B7 to the M38, M39, and M40 metabolites. The M12 metabolite is either dealkylated to the M32 metabolite or oxidized and hydrolyzed to M13. M13 is dealkylated to M32, which is reduced and oxidized to M48.

来源:DrugBank

毒理性

• 肝毒性

在ponesimod的预先注册试验中，血清ALT升高是常见的（高达23%的受试者），但通常是轻微和无症状的，即使在继续治疗或在停止治疗几个月内也会恢复到基线值。在一项前瞻性、仔细监测的试验中，ponesimod接受者的血清转氨酶升高超过正常上限3倍（ULN）的报告比例为17%，超过5倍ULN的比例为4.6%。在这些上市前的临床试验中，没有出现急性肝炎或临床明显的黄疸型肝损伤的情况，但肝功能测试升高导致至少2%的受试者提前终止治疗。尽管ponesimod与淋巴细胞减少相关，长期治疗与单纯疱疹和带状疱疹感染复发的风险相关，但尚未有报道称其与乙型肝炎复发病例有关联，尽管有报道称使用fingolimod出现过一例此类情况。因此，在治疗期间，轻到中度且短暂的血清酶升高是常见的，但尚未有报道称ponesimod会导致临床上明显的黄疸型肝损伤，尽管使用它的临床经验有限。

In preregistration trials of ponesimod, serum ALT elevations were common (in up to 23% of recipients) but were typically mild and asymptomatic, returning to baseline values even with continuation of therapy or within a few months of stopping. In one prospective, carefully monitored trial, serum aminotransferase elevations above 3 times upper limit of normal (ULN) were reported in 17% of ponesimod recipients and above 5 times ULN in 4.6%. In these prelicensure clinical trials, there were no cases of acute hepatitis or clinically apparent liver injury with jaundice, but elevations in liver tests led to early discontinuation in at least 2% of subjects. While ponesimod is associated with lymphopenia and long-term therapy is associated with risk for reactivation of herpes simplex and zoster infections, it has not been linked to cases of reactivation of hepatitis B although one such case has been reported with fingolimod. Thus, mild-to-moderate and transient serum enzyme elevations during therapy are common, but clinically apparent liver injury with jaundice due to ponesimod has not been reported, although the clinical experience with its use has been limited.

来源:LiverTox

毒理性

• 在妊娠和哺乳期间的影响

◉ 母乳喂养期间使用总结：尽管泊尼莫德在母体血浆中高度结合，不太可能大量进入母乳，但它对哺乳婴儿可能具有潜在毒性。由于没有关于母乳喂养期间使用泊尼莫德的已发表经验，专家意见通常建议应避免使用与之密切相关的药物芬戈利莫德，尤其是在哺乳新生儿或早产儿时。然而，制造商的标签并未建议在哺乳期间避免使用泊尼莫德。 ◉ 对哺乳婴儿的影响：截至修订日期，未找到相关的已发表信息。 ◉ 对泌乳和母乳的影响：截至修订日期，未找到相关的已发表信息。

◉ Summary of Use during Lactation:Although ponesimod is highly bound in maternal plasma and unlikely to reach the breastmilk in large amounts, it is potentially toxic to the breastfed infant. Because there is no published experience with ponesimod during breastfeeding, expert opinion generally recommends that the closely related drug fingolimod should be avoided during breastfeeding, especially while nursing a newborn or preterm infant. However, the manufacturer's labeling does not recommend against the use of ponesimod in breastfeeding. ◉ Effects in Breastfed Infants:Relevant published information was not found as of the revision date. ◉ Effects on Lactation and Breastmilk:Relevant published information was not found as of the revision date.

来源:Drugs and Lactation Database (LactMed)

毒理性

• 蛋白质结合

Ponesimod在血浆中与蛋白质的结合率超过99%。尽管文献中尚未明确它所结合的蛋白质。

Ponesimod is >99% protein bound in plasma. Though the proteins it binds to have not been identified in literature.

来源:DrugBank

吸收、分配和排泄

• 吸收

一个 10 毫克口服剂量的泊尼莫德生物利用度为 84%。泊尼莫德达到最大浓度 (Cmax) 为 109 纳克/毫升，达到最大浓度的时间 (Tmax) 为 4.0 小时，并且曲线下面积 (AUC) 为 3872 小时*纳克/毫升。

A 10mg oral dose of ponesimod is 84% bioavailable. Ponesimod reaches a Cmax of 109 ng/mL, with a Tmax of 4.0 hours, and an AUC of 3872 h\*ng/mL.

来源:DrugBank

吸收、分配和排泄

• 消除途径

57.3-79.6%的口服放射性剂量在粪便中回收，其中16-26%为未代谢的母化合物，22%为M12代谢物。10.3-18.4%的口服剂量通过尿液排出。0.6-1.9%的放射性剂量以呼出的二氧化碳形式回收。

57.3-79.6% of a radiolabelled oral dose is recovered in the feces, with 16-26% as the unmetabolized parent compound and 22% as the M12 metabolite. 10.3-18.4% of an oral dose is eliminated in the urine. 0.6-1.9% of a radiolabelled dose was recovered as expired CO₂.

来源:DrugBank

吸收、分配和排泄

• 分布容积

在稳态下，ponesimod的分布容积为160升。

The volume of distribution of ponesimod at steady state is 160 L.

来源:DrugBank

吸收、分配和排泄

• 清除

Ponesimod的清除率为3.8 L/h。

The clearance of ponesimod is 3.8 L/h.

来源:DrugBank

安全信息

• 危险性防范说明：
  P261,P305+P351+P338
• 危险性描述：
  H302,H315,H319,H335

制备方法与用途

生物活性

Ponesimod（ACT-128800）是一种具有口服活性的S1P1免疫调节剂，其EC50值为5.7 nM。

靶点

Target	Value
S1P1 receptor (In recombinant Chinese hamster ovary cells)	5.7 nM(EC50)

体外研究

与S1P相比，ponesimod对人源重组受体S1P1的调节效能高4.4倍，而对S1P3的调节效能低150倍。因此，ponesimod相对于S1P3的选择性比天然配体高出约650倍。

体内研究

Ponesimod是一种新型且有效的选择性S1P1受体激动剂，在迟发型过敏小鼠皮肤中能阻止水肿形成、炎症细胞聚集以及细胞因子的释放。在佐剂型关节炎大鼠模型中，ponesimod可以防止足趾体积增大及关节炎症。通过选择性激活S1P1，ponesimod导致外周血淋巴细胞减少，并且能够阻止由淋巴细胞介导的组织炎症。因此，ponesimod可能在自身免疫动物模型和人类自身免疫疾病中发挥治疗作用。停用后一周内，Ponesimod会被迅速消除，其药效可逆。

反应信息

• 作为产物：
  描述：

  (2Z,5Z)-5-(3-chloro-4-hydroxybenzylidene)-2-propylimino-3-o-tolylthiazolidin-4-one 、 (R)-(-)-3-氯-1,2-丙二醇 在 (R)-(-)-3-氯-1,2-丙二醇 作用下， 以84的产率得到珀奈莫德;
  参考文献：
  名称：

  [EN] PROCESS FOR THE PREPARATION OF|(2Z,5Z)-5-(3-CHLORO-4-((R)-2,3-DIHYDROXYPROPOXY)BENZYLIDENE)-2-(PROPYLIMINO)-3-|(O-TOLYL)THIAZOLIDIN-4-ONE AND INTERMEDIATE USED IN SAID PROCESS
  [FR] PROCÉDÉ DE PRÉPARATION DE (2Z,5Z)-5-(3-CHLORO-4-((R)-2,3-DIHYDROXYPROPOXY)BENZYLIDENE)-2-(PROPYLIMINO)-3-|(O-TOLYL)THIAZOLIDIN-4-ONE ET INTERMÉDIAIRE UTILISÉ DANS LEDIT PROCÉDÉ

  摘要：

  本发明涉及一种制备(2Z,5Z)-5-(3-氯-4-((R)-2,3-二羟丙氧基)苯甲醛基)-2-(丙基亚胺基)-3-(o-甲苯基)噻唑啉-4-酮的新工艺，以及在该工艺中使用的新中间体(R)-3-氯-4-(2,3-二羟丙氧基)苯甲醛。(2Z,5Z)-5-(3-氯-4-((R)-2,3-二羟丙氧基)苯甲醛基)-2-(丙基亚胺基)-3-(o-甲苯基)噻唑啉-4-酮在WO 2005/054215中被描述为免疫抑制剂。本发明还涉及一种制备(R)-3-氯-4-(2,3-二羟丙氧基)苯甲醛的新工艺。

  公开号：

  WO2014027330A1

文献信息

• [EN] 5-(BENZ- (Z) -YLIDENE) -THIAZOLIDIN-4-ONE DERIVATIVES AS IMMUNOSUPPRESSANT AGENTS<br/>[FR] DERIVES DE 5-(BENZ-(Z)-YLIDENE)-THIAZOLIDINE-4-ONE UTILISES COMME AGENT IMMUNODEPRESSEURS
  申请人：ACTELION PHARMACEUTICALS LTD

  公开号：WO2005054215A1

  公开（公告）日：2005-06-16

  The invention relates to pharmaceutical compositions containing at least one 5- (benz- (Z) -ylidene-thiazolidin-4-one derivative (I), to prevent or treat disorders associated with an activated immune system. Furthermore, the invention relates to novel thiazolidin-4-one derivatives notably for use as pharmaceutically active compounds. Said compounds particularly act also as immunosuppressive agents.

  本发明涉及药物组合物，其包含至少一种5-(苯基(Z)-亚胺基噻唑啉-4-酮衍生物(I))，用于预防或治疗与激活的免疫系统相关的疾病。此外，本发明还涉及新的噻唑啉-4-酮衍生物，特别用于作为药物活性化合物。这些化合物特别还具有免疫抑制剂的作用。
• [EN] PROCESS FOR THE PREPARATION OF|(2Z,5Z)-5-(3-CHLORO-4-((R)-2,3-DIHYDROXYPROPOXY)BENZYLIDENE)-2-(PROPYLIMINO)-3-|(O-TOLYL)THIAZOLIDIN-4-ONE AND INTERMEDIATE USED IN SAID PROCESS<br/>[FR] PROCÉDÉ DE PRÉPARATION DE (2Z,5Z)-5-(3-CHLORO-4-((R)-2,3-DIHYDROXYPROPOXY)BENZYLIDENE)-2-(PROPYLIMINO)-3-|(O-TOLYL)THIAZOLIDIN-4-ONE ET INTERMÉDIAIRE UTILISÉ DANS LEDIT PROCÉDÉ
  申请人：ACTELION PHARMACEUTICALS LTD

  公开号：WO2014027330A1

  公开（公告）日：2014-02-20

  The present invention relates to a new process for the preparation of (2Z,5Z)-5-(3-chloro-4- ((R)-2,3-dihydroxypropoxy)benzylidene)-2-(propylimino)-3-(o-tolyl)thiazolidin-4-one and to the new intermediate (R)-3-chloro-4-(2,3-dihydroxypropoxy)-benzaldehyde used in this process. (2Z,5Z)-5-(3-Chloro-4-((R)-2,3-dihydroxypropoxy)benzylidene)-2-(propylimino)-3- (o-tolyl)thiazolidin-4-one is described in WO 2005/054215 to act as an immunosuppressive agent. The present invention further also relates to a new process for the preparation of (R)-3-chloro-4-(2,3-dihydroxypropoxy)-benzaldehyde.

  本发明涉及一种制备(2Z,5Z)-5-(3-氯-4-((R)-2,3-二羟丙氧基)苯甲醛基)-2-(丙基亚胺基)-3-(o-甲苯基)噻唑啉-4-酮的新工艺，以及在该工艺中使用的新中间体(R)-3-氯-4-(2,3-二羟丙氧基)苯甲醛。(2Z,5Z)-5-(3-氯-4-((R)-2,3-二羟丙氧基)苯甲醛基)-2-(丙基亚胺基)-3-(o-甲苯基)噻唑啉-4-酮在WO 2005/054215中被描述为免疫抑制剂。本发明还涉及一种制备(R)-3-氯-4-(2,3-二羟丙氧基)苯甲醛的新工艺。
• J. Med. Chem. 2010, 53, 4198-4211
  作者：

  DOI：——

  日期：——
• WO2008062376A2
  申请人：——

  公开号：——

  公开（公告）日：——