4-amino-5-chloro-N-[(3R)-1-[3-(4-fluorophenoxy)propyl]-3-methoxypiperidin-4-yl]-2-methoxybenzamide | 260779-88-2

• 物质功能分类: 分析化学 - 对照品
• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: 4-amino-5-chloro-N-[(3R)-1-[3-(4-fluorophenoxy)propyl]-3-methoxypiperidin-4-yl]-2-methoxybenzamide
• CAS: 260779-88-2；81098-60-4
• 化学式: C₂₃H₂₉ClFN₃O₄
• 分子量: 465.9
• InChiKey: DCSUBABJRXZOMT-LWMIZPGFSA-N

物化性质

• 溶解度：
  二甲基亚砜：~30mg/毫升
• 颜色/状态：
  White to slightly biege powder
• 气味：
  Odorless

计算性质

• 辛醇/水分配系数(LogP)：
  3.4
• 重原子数：
  32
• 可旋转键数：
  9
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.43
• 拓扑面积：
  86
• 氢给体数：
  2
• 氢受体数：
  7

ADMET

代谢

IPA 版权：ASHP 使用狗、兔子和大鼠的肝脏部分在体外对西沙必利的代谢进行了研究，并通过高效液相色谱和质谱鉴定了代谢物。主要的生物转化途径包括在哌啶氮上发生的氧化N-脱烷基化以及在氟苯基或苯甲酰胺基团上发生的芳香羟基化。ENG ~21 nq~_~n_~。

IPA COPYRIGHT: ASHP The metabolism of cisapride in vitro using Liver fractions of dogs, rabbits, and rats and the metabolites identified by high performance LC and by MS are described. Main bi otransformat i on routes were oxi dat i ve N-dealkylat i on at the pi peri di ne ni trogen and aron at i c hydroxylat i on at the fluorophenyl or at the benzami de moi ety. ENG ~21 nq~_~n_~.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 肝毒性

西沙必利和替加色罗在治疗期间都与偶尔的血清酶水平升高有关（1%至9%），但这些升高通常是轻微且无症状的，有或没有停药都会迅速解决。虽然在使用5-HT4受体激动剂治疗期间有描述过中度的血清酶升高，但没有确切的报告表明这些药物会导致临床上明显的急性肝损伤和黄疸。普芦卡必利并未与血清酶水平升高率增加或急性肝损伤和黄疸的实例有关联，但其长期使用的经验有限。

Both cisapride and tegaserod were linked to occasional instances of serum enzyme elevations during therapy (1% to 9%), but these elevations were generally mild and asymptomatic, resolving rapidly with or without discontinuing drug. While moderate serum enzyme elevations during 5-HT4 receptor agonist therapy have been described, there have been have been no convincing reports of clinically apparent acute liver injury with jaundice attributed to these agents. Plucalopride has not been linked to increased rates of serum enzyme elevations nor to instances of acute liver injury with jaundice, but experience with its long-term use has been limited.

来源:LiverTox

毒理性

• 相互作用

Cispride 被报告可以提高 / 酒精或苯二氮卓类药物 / 的吸收速率。

Cispride has been reported to increase the rate of absorption of /alcohol or benzodiazepines/.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

与抗胆碱药或其他具有抗胆碱活性的药物同时使用可能会拮抗西沙必利对胃肠动力的影响。

Concurrent use /with anticholinergics or other medications with anticholinergic activity/ may antagonize the effects of cisapride on gastrointestinal motility.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

西沙必利加速西咪替丁和雷尼替丁的吸收。

Cisapride accelerates the absorption of cimetidine and rantidine.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

伊曲康唑、酮康唑或静脉注射咪康唑与西沙必利的联合使用是禁忌的；同时使用可能导致通过这些抗真菌药物抑制细胞色素P450代谢途径而使西沙必利的血浆浓度升高；这已导致接受西沙必利和酮康唑治疗的患者出现室性心律失常，包括尖端扭转型室速。

Concurrent use of itraconazole, ketoconazole, or intravenous miconazole with cisapride is contraindicated; concurrent use may result in elevated plasma concentrations of cisapride through inhibition of the cytochrome p450 metabolic pathways by these antifungals; this has led to ventricular arrhythmias, including torsades des pointes, in patients taking cisapride and ketoconazole.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

研究了 cisapride（一种新的促动力药）在绵羊模型中的胎盘传递。通过从慢性植入动脉导管中获取血样，研究了羔羊、怀孕母羊和胎儿的cisapride药代动力学。羔羊和成年绵羊的药代动力学参数相似：半衰期为1.39-1.83小时；总血浆清除率为1998-2160 ml/kg/小时；AUC为92.6-100.1 ng·小时/毫升。根据静脉注射后获得的参数，可以正确预测持续输注后的cisapride血浆浓度。在给母羊单次静脉注射后，存在母子传递的cisapride。Cisapride在给药后5分钟内穿过胎盘，并在给药后20至30分钟内与母体血浆达到平衡。平均胎儿至母体血浆浓度比为0.71。羊水中也含有可测量的cisapride。母体和胎儿血浆中cisapride的蛋白结合率分别为89.0%和88.4%；自由分数是人类中的4倍。Cisapride穿过绵羊胎盘屏障。绵羊胎盘的透过性低于人类胎盘，但cisapride更高的自由分数促进了胎盘传递。

The placental transfer of cisapride, a new prokinetic agent, was studied in a sheep model. The pharmacokinetics of cisapride were studied in the lamb, the pregnant ewe, and the fetus by obtaining blood samples from chronically implanted arterial catheters. Comparable pharmacokinetic parameters were found in the lamb and the adult sheep: half-life, 1.39-1.83 hr; total plasma clearance, 1998-2160 ml/kg/hr; AUC, 92.6-100.1 ng.hr/ml. Cisapride plasma concentrations after continuous infusion were predicted correctly based on the parameters obtained after IV bolus. There was a materno-fetal transfer of cisapride following a single IV bolus administered to the mother. Cisapride crossed the placenta within 5 min and equilibrated with maternal plasma within 20 to 30 min after dosing. The average fetal-to-maternal plasma concentration ratio was 0.71. The amniotic fluid also contained measurable amounts of cisapride. The protein binding of cisapride in maternal and fetal plasma is 89.0% and 88.4%, respectively; the free fraction is 4 times larger than in humans. Cisapride crosses the ovine placental barrier. The sheep placenta is less permeable than the human placenta, but the higher free fraction of cisapride facilitates placental transfer.

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 危险品标志：
  Xi
• 安全说明：
  S26,S39
• 危险类别码：
  R41
• WGK Germany：
  2
• 海关编码：
  2933399090

制备方法与用途

生物活性

Cisapride（Propulsid, Alimix, Propulsin, Enteropride, Kinestase）是一种直接且选择性的5-HT4受体激动剂，IC50值为0.483 μM。同时，它也具有间接的拟副交感神经作用。

靶点

Target	Value
5-HT4 receptor (Cell-free assay)	0.483 μM
hERG (Cell-free assay)	<1 μM

体外研究

Cisapride能够抑制血管中的Kv电流，而不依赖于血清素5-HT4受体的激活。作为HERG通道的阻滞剂，Cisapride可通过改变细胞周期分布、诱导凋亡来抑制胃癌细胞的生长，因此对于治疗胃癌有潜在的价值。Cisapride通过对HERG通道时间依赖式和剂量依赖式的阻滞作用，抑制人类胃癌细胞的生长和集落生成，而对GES细胞的影响较小。

体内研究

Cisapride广泛用于治疗胃肠蠕动障碍，如食道胃酸逆流异常、假性肠梗阻、慢传输型便秘胃轻瘫。尽管Cisapride是一种有效的促胃肠动力药，但其常见的副作用包括腹痛、恶心、腹泻和频尿。在大鼠中的药代动力学数据显示，Cisapride的半衰期（T1/2）为1.48小时。