cisapride | 81098-60-4

• 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 - 苯酚醚
• 英文名称: cisapride
• 英文别名: Propulsid；4-amino-5-chloro-N-[1-[3-(4-fluorophenoxy)propyl]-3-methoxypiperidin-4-yl]-2-methoxybenzamide
• CAS: 81098-60-4；260779-88-2
• 化学式: C₂₃H₂₉ClFN₃O₄
• 分子量: 465.952
• InChiKey: DCSUBABJRXZOMT-UHFFFAOYSA-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
• 稳定性/保质期：
  按规定使用和贮存时不会分解，并应避免接触氧化剂。

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进行氧化N-脱烷基化以及在氟苯基或苯甲酰胺基上进行芳香族羟基化。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)

代谢

(-+)-西沙必利已知的人体代谢物包括去甲西沙必利、4-氟-2-羟基西沙必利和3-氟-4-羟基西沙必利。

(+-)-Cisapride has known human metabolites that include Norcisapride, 4-Fluoro-2-hydroxycisapride, and 3-Fluoro-4-hydroxycisapride.

来源:NORMAN Suspect List Exchange

毒理性

• 在妊娠和哺乳期间的影响

◉ 母乳喂养期间使用总结：由于心脏毒性，美国食品药品监督管理局从美国市场撤回了西沙必利。由于母乳中西沙必利含量较低，如果需要的话，哺乳期母亲可以使用。 ◉ 对哺乳婴儿的影响：截至修订日期，未找到相关已发布信息。 ◉ 对泌乳和母乳的影响：截至修订日期，未找到相关已发布信息。

◉ Summary of Use during Lactation:Cisapride was removed from the market in the United States by the U.S. Food and Drug Administration because of cardiac toxicity. Because of the low levels of cisapride in breastmilk, its use is acceptable in nursing mothers if it is required. ◉ 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

• 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血药浓度升高；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

cisapride是一种新的促动力药，其在绵羊模型中的胎盘传递进行了研究。通过从慢性植入的动脉导管获取血液样本，研究了羔羊、怀孕母羊和胎儿的cisapride药代动力学。在羔羊和成年绵羊中发现了相似的药代动力学参数：半衰期，1.39-1.83小时；总血浆清除率，1998-2160 ml/kg/小时；AUC，92.6-100.1 ng·小时/ml。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，发生了cisapride的母婴传递。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%；自由分数比人类高出4倍。cisapride穿过绵羊胎盘屏障。绵羊胎盘的透性低于人类胎盘，但cisapride更高的自由分数有助于胎盘传递。

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
• RTECS号：
  CU9372000
• 海关编码：
  2942000000
• 危险性防范说明：
  P305+P351+P338
• 危险性描述：
  H319
• 储存条件：
  请将药品存放在密闭、阴凉、干燥的地方。

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。

反应信息

• 作为反应物：
  描述：

  cisapride 以54%的产率得到Cis-4-amino-5-chloro-N-{1-[3-(4-fluorophenoxy)propyl]-3-methoxy-4-piperidinyl}-2-hydroxybenzamide
  参考文献：
  名称：

  Pharmacologically active substituted benzamides

  摘要：

  式中R1、R2、R3、R4、R5和A为本发明所定义的取代苯甲酰胺类新化合物，用于治疗呕吐，特别是癌症患者的化疗诱导呕吐。其中一些化合物也用于治疗与胃动力受损相关的疾病。

  公开号：

  US04808624A1
• 作为产物：
  描述：

  4-amino-5-chloro-N-[1-[3-(4-fluorophenoxy)propyl]-3-methoxypyridin-1-ium-4-yl]-2-methoxybenzamide 以73.9的产率得到cisapride
  参考文献：
  名称：

  ES2007259A6

  摘要：

  公开号：

文献信息

• [EN] SULFONYL COMPOUNDS THAT INTERACT WITH GLUCOKINASE REGULATORY PROTEIN<br/>[FR] COMPOSÉS DE SULFONYLE QUI INTERAGISSENT AVEC LA PROTÉINE RÉGULATRICE DE LA GLUCOKINASE
  申请人：AMGEN INC

  公开号：WO2013123444A1

  公开（公告）日：2013-08-22

  The present invention relates to sulfonyl compounds that interact with glucokinase regulatory protein. In addition, the present invention relates to methods of treating type 2 diabetes, and other diseases and/or conditions where glucokinase regulatory protein is involved using the compounds, or pharmaceutically acceptable salts thereof, and pharmaceutical compositions that contain the compounds, or pharmaceutically acceptable salts thereof.

  本发明涉及与葡萄糖激酶调节蛋白相互作用的磺酰基化合物。此外，本发明涉及使用这些化合物或其药学上可接受的盐治疗2型糖尿病和其他涉及葡萄糖激酶调节蛋白的疾病和/或症状的方法，以及含有这些化合物或其药学上可接受的盐的药物组合物。
• [EN] INDAZOLE- AND PYRROLOPYRIDINE-DERIVATIVE AND PHARMACEUTICAL USE THEREOF<br/>[FR] DÉRIVÉ D'INDAZOLE ET PYRROLOPYRIDINE ET UTILISATION PHARMACEUTIQUE DE CELUI-CI
  申请人：DAINIPPON SUMITOMO PHARMA CO

  公开号：WO2012169649A1

  公开（公告）日：2012-12-13

  The present invention relates to a novel indazole- or pyrrolopyridine-derivative, represented by the formula (1) below, that has an agonistic action or a partial agonistic action against serotonin-4 receptor, and a pharmaceutical composition comprising the same. Formula (1) [wherein each substituent is as defined in claim 1]

  本发明涉及一种新型吲唑基或吡咯吡啶基衍生物，由下面的式（1）表示，该衍生物对5-羟色胺-4受体具有激动作用或部分激动作用，并且包括含有该衍生物的药物组合物。式（1）[其中每个取代基如权利要求1所定义]
• HETEROCYCLIC COMPOUNDS FOR THE INHIBITION OF PASK
  申请人：McCall John M.

  公开号：US20140128392A1

  公开（公告）日：2014-05-08

  Disclosed herein are new heterocyclic compounds of Formula IIa: and compositions thereof, and their application as pharmaceuticals for the treatment of disease. Methods of inhibiting PAS Kinase (PASK) activity in a human or animal subject are also provided for the treatment of diseases such as diabetes mellitus.

  本文披露了新的Formula IIa的杂环化合物及其组合物，以及它们作为治疗疾病的药物的应用。还提供了在人类或动物主体中抑制PAS激酶（PASK）活性的方法，用于治疗糖尿病等疾病。
• PYRAZOLYL-CONTAINING TRICYCLIC DERIVATIVE, PREPARATION METHOD THEREFOR AND USE THEREOF
  申请人：Jiangsu Hansoh Pharmaceutical Group Co., Ltd.

  公开号：US20200247815A1

  公开（公告）日：2020-08-06

  The present invention relates to pyrazolyl-containing tricyclic derivative, a preparation method therefor and the use thereof. In particular, the present invention relates to a compound as shown in the general formula (I), a preparation method therefor and a pharmaceutical composition containing the compound, and the use thereof as a protease such as ERK (MAPK) inhibitor in the treatment of cancers, bone diseases, inflammatory diseases, immunological diseases, nervous system diseases, metabolic diseases, respiratory diseases and heart diseases, wherein the definition of each substituent in the general formula (1) is the same as defined in the description.

  本发明涉及吡唑基含有的三环衍生物，其制备方法及其用途。具体而言，本发明涉及一种如通式(I)所示的化合物，其制备方法及含有该化合物的药物组合物，以及将其用作蛋白酶，如ERK（MAPK）抑制剂，用于治疗癌症、骨疾病、炎症性疾病、免疫疾病、神经系统疾病、代谢性疾病、呼吸系统疾病和心脏疾病，其中通式（1）中每个取代基的定义与描述中定义的相同。
• ANTHELMINTIC COMPOUNDS AND COMPOSITIONS AND METHOD OF USING THEREOF
  申请人：Meng Charles Q.

  公开号：US20140142114A1

  公开（公告）日：2014-05-22

  The present invention relates to novel anthelmintic compounds of formula (I) below: wherein Y and Z are independently a bicyclic carbocyclic or a bicyclic heterocyclic group, or one of Y or Z is a bicyclic carbocyclic or a bicyclic heterocyclic group and the other of Y or Z is alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, heterocyclyl or heteroaryl, and variables X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 and X 8 are as defined herein. The invention also provides for veterinary compositions comprising the anthelmintic compounds of the invention, and their uses for the treatment and prevention of parasitic infections in animals.

  本发明涉及以下式（I）的新型驱虫化合物： 其中 Y和Z分别是双环碳环或双环杂环基团，或者Y或Z中的一个是双环碳环或双环杂环基团，另一个是烷基，烯基，炔基，环烷基，苯基，杂环基或杂芳基，以及变量X 1 ，X 2 ，X 3 ，X 4 ，X 5 ，X 6 ，X 7 和X 8 如本文所定义。本发明还提供了包含本发明的驱虫化合物的兽药组合物，以及它们用于治疗和预防动物寄生虫感染的用途。