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Cisapride

HCID 178923504
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Grundinformationen

CAS
86718-70-9
Standard-SMILES
COc1cc(N)c(Cl)cc1C(=O)N[C@@H]1CCN(CCCOc2ccc(F)cc2)C[C@@H]1OC
InChIKey
DCSUBABJRXZOMT-IRLDBZIGSA-N
Summenformel
C23H29ClFN3O4
Durchschnittliche Molmasse
465,9 g/mol

Überblick

Cisapride is the amide resulting from formal condensation of 4-amino-5-chloro-2-methoxybenzoic acid with cis-1-[3-(4-fluorophenoxy)propyl]-3-methoxypiperidin-4-amine. It has been used (as its monohydrate or as its tartrate) for the treatment of gastro-oesophageal reflux disease and for non-ulcer dyspepsia, but its propensity to cause cardiac arrhythmias resulted in its complete withdrawal from many countries, including the U.K., and restrictions on its use elsewhere. It has a role as a serotonergic agonist, an anti-ulcer drug and a gastrointestinal drug. It is a member of benzamides, a member of piperidines, an aromatic ether, an organofluorine compound, a substituted aniline and a member of monochlorobenzenes.

Namen und Bezeichner

Bevorzugter Name
Cisapride
IUPAC
4-amino-5-chloro-N-[(3S,4R)-1-[3-(4-fluorophenoxy)propyl]-3-methoxypiperidin-4-yl]-2-methoxybenzamide
Englischer Name
(+)-Cisapride
Molmasse
0

Namen und Synonyme

cisapride81098-60-4CisapridaCisapridumEnteroprideKinestasePridesiaPrepulsidR 51619CHEBI:3720UVL329170W4-amino-5-chloro-N-[(3S,4R)-1-[3-(4-fluorophenoxy)propyl]-3-methoxypiperidin-4-yl]-2-methoxybenzamide
Weitere Namen anzeigen
cis-4-Amino-5-chloro-N-(1-(3-(p-fluorophenoxy)propyl)-3-methoxy-4-piperidyl)-o-anisamideR-51,619R-51619Benzamide, 4-amino-5-chloro-N-(1-(3-(4-fluorophenoxy)propyl)-3-methoxy-4-piperidinyl)-2-methoxy-, cis-DTXSID30228254-amino-5-chloro-N-((3S,4R)-1-(3-(4-fluorophenoxy)propyl)-3-methoxypiperidin-4-yl)-2-methoxybenzamidePrepulsid quickletcis-4-amino-5-chloro-N-(1-(3-(p-fluorophenoxy)propyl)-3-methoxy-4-piperidinyl)-o-anisamide

Datenbank-Bezeichner

CAS
86718-70-9
ChEMBL
CHEMBL1729、CHEMBL560739
ChEBI
CHEBI:3720
UNII
UVL329170W
EC Number
279-689-7、623-862-5
Nikkaji
J239.729C

Eigenschaften

Berechnete Struktureigenschaften

XLogP
3,4
Polarare Oberfläche (TPSA)
86,1 Ų
H-Brücken-Donoren
2
H-Brücken-Akzeptoren
7
Frei drehbare Bindungen
9
Schwere Atome
32
Formalladung
0
Komplexität
581

Experimentelle und physikochemische Eigenschaften

DrugsPharmaceuticals -> Listed in ZINC15
LogP3.3
OdorOdorless
Color/FormWhite to slightly biege powder
Solubility · 3 Einträge

Sparingly soluble in methanol. Soluble in acetone

Practically insoluble in water.

1.20e-02 g/L

Human DrugsBreast Feeding; Lactation; Gastrointestinal Agents; Serotonin Agonists;
Melting Point110 °C
Physical DescriptionSolid
Other Experimental Properties · 2 Einträge

Crystals from 2-propanol /monohydrate/

109.8 °C /monohydrate/

Sicherheit und Regulatorisches

Sicherheitsangaben dienen nur zur Orientierung und ersetzen weder das Sicherheitsdatenblatt (SDB) des Lieferanten noch geltende Vorschriften oder eine fachliche Bewertung.

GHS-Klassifizierung

GHS Classification · 6 Einträge

Danger

H318 (100%): Causes serious eye damage [Danger Serious eye damage/eye irritation]

P264+P265, P280, P305+P354+P338, and P317 (click each P-code to see the statement)

Aggregated GHS information provided per 38 reports by companies from 1 notifications to the ECHA C&L Inventory.

Danger

H318 (100%): Causes serious eye damage [Danger Serious eye damage/eye irritation]

Gefahrenhinweise

Other Safety InformationIMAP assessments - Benzamide, 4-amino-5-chloro-N-[1-[3-(4-fluorophenoxy)propyl]-3-methoxy-4-piperidinyl]-2-methoxy-, cis-: Environment tier I assessment
FDA Requirements · 1 Eintrag

Manufacturers, packers, and distributors of drug and drug products for human use are responsible for complying with the labeling, certification, and usage requirements as prescribed by the Federal Food, Drug, and Cosmetic Act, as amended (secs 201-902, 52 Stat. 1040 et seq., as amended; 21 U.S.C. 321-392).

Hazard Classes and Categories · 2 Einträge

Eye Dam. 1 (100%)

Eye Dam. 1 (100%)

Sicherheit und Schutzausrüstung

Disposal Methods · 1 Eintrag

SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices.

Chemie und Industrie

Pharmakologische Informationen

ATC Code · 2 Einträge

A - Alimentary tract and metabolism

QA - Alimentary tract and metabolism

Protein Binding97.5%
Pharmacodynamics · 1 Eintrag

Cisapride is a parasympathomimetic which acts as a serotonin 5-HT<sub>4</sub> agonist; upon activation of the receptor signaling pathway, cisapride promotes the release of acetylcholine neurotransmitters in the enteric nervous system. Cisapride stimulates motility of the upper gastrointestinal tract without stimulating gastric, biliary, or pancreatic secretions. Cisapride increases the tone and amplitude of gastric (especially antral) contractions, relaxes the pyloric sphincter and the duodenal bulb, and increases peristalsis of the duodenum and jejunum resulting in accelerated gastric emptying and intestinal transit. It increases the resting tone of the lower esophageal sphincter. It has little, if any, effect on the motility of the colon or gallbladder. Cisapride does not induce muscarinic or nicotinic receptor stimulation, nor does it inhibit acetylcholinesterase activity.

Mechanism of Action · 2 Einträge

Cisapride acts through the stimulation of the serotonin 5-HT<sub>4</sub> receptors which increases acetylcholine release in the enteric nervous system (specifically the myenteric plexus). This results in increased tone and amplitude of gastric (especially antral) contractions, relaxation of the pyloric sphincter and the duodenal bulb, and increased peristalsis of the duodenum and jejunum resulting in accelerated gastric emptying and intestinal transit.

Cisapride exerts its effect by increasing the release of acetylcholine from the postganglionic nerve endings of the myenteric plexus. This release of acetylcholine increases esophageal activity and increases esophageal sphincter tone, thereby improving esophageal clearance and decreasing reflux of gastric and duodenal emptying as a result of increased gastric and duodenal contractility and antroduodenal coordination. Duodenogastric reflux is also decreased. Cisapride improves transit in both small and large bowel.

Biological Half-Life6-12 hours
Metabolism/Metabolites

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Toxikologische Informationen

Treatment · 1 Eintrag

In instances of overdose, patients should be evaluated for possible QT prolongation and ventricular arrhythmias, including torsades de pointes. Treatment should include gastric lavage and/or activated charcoal, close observation and general supportive measures. (L1712)

Interactions · 5 Einträge

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

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

Cisapride accelerates the absorption of cimetidine and rantidine.

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.

For more Interactions (Complete) data for CISAPRIDE (8 total), please visit the HSDB record page.

Exposure RoutesCisapride is rapidly absorbed after oral administration, with an absolute bioavailability of 35-40%.
Toxicity Summary · 1 Eintrag

Cisapride acts through the stimulation of the serotonin 5-HT<sub>4</sub> receptors which increases acetylcholine release in the enteric nervous system (specifically the myenteric plexus). This results in increased tone and amplitude of gastric (especially antral) contractions, relaxation of the pyloric sphincter and the duodenal bulb, and increased peristalsis of the duodenum and jejunum resulting in accelerated gastric emptying and intestinal transit.

Signs and SymptomsDiarrhea, upset stomach, stomach discomfort, vision changes, constipation.
Human Toxicity ExcerptsNo mutagenicity was demonstrated in the following in vitro and in vivo models: ... chromosomal aberration assay on human lymphocytes ... .
Carcinogen ClassificationNo indication of carcinogenicity to humans (not listed by IARC).
Drug Induced Liver Injury · 5 Einträge

Drug-Induced Liver Injury Severity and Toxicity (DILIst)

Cisapride

DILI Negative

Oral

DOI:10.1016/j.drudis.2019.09.022

Non-Human Toxicity Excerpts · 3 Einträge

No tumorigenicity was demonstrated in rats receiving up to 80 mg of cisapride/kg of body weight (mg/kg) (50 times the maximum recommended human dose for a 50 kg person) a day for 25 months or in mice receiving up to 80 mg/kg ( 50 times the maximum recommended human dose) of cisapride a day for 19 months.

No mutagenicity was demonstrated in the following in vitro and in vivo models: Ames' test, ... sex-linked recessive lethal test in Drosophila melanogaster, dominant lethal test in male and female mice germ cells and micronucleus test in rats.

At oral doses of up to 160 mg/kg a day (100 times the maximum recommended human dose), cisapride was found to have no effect on fertility in male rats. In female rats at oral doses of 40 mg/kg a day and higher, cisapride prolonged the breeding interval required for impregnation. These effects were also observed at maturity in the female offspring of female rats treated with oral doses of cisapride at 10 mg/kg a day or higher. At dose of 160 mg/kg a day, cisapride exerted contragestational/pregnancy disrupting effects in female rats.

Antidote and Emergency TreatmentFor treatment of overdose: Recommended treatment consists of the following: Stopping administration of medication. Use of gastric lavage and/or administration of activated charcoal. Supportive therapy.
Effects During Pregnancy and Lactation◉ Summary of Use during Lactation

Regulatorische Informationen

FDA Requirements · 1 Eintrag

Manufacturers, packers, and distributors of drug and drug products for human use are responsible for complying with the labeling, certification, and usage requirements as prescribed by the Federal Food, Drug, and Cosmetic Act, as amended (secs 201-902, 52 Stat. 1040 et seq., as amended; 21 U.S.C. 321-392).

· 3 Einträge

Hepatic. Extensively metabolized via cytochrome P450 3A4 enzyme.

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_~.

Hepatic. Extensively metabolized via cytochrome P450 3A4 enzyme. Half Life: 6-12 hours

MeSH Pharmacological Classification · 3 Einträge

Various agents with different action mechanisms used to treat or ameliorate PEPTIC ULCER or irritation of the gastrointestinal tract. This has included ANTIBIOTICS to treat HELICOBACTER INFECTIONS; HISTAMINE H2 ANTAGONISTS to reduce GASTRIC ACID secretion; and ANTACIDS for symptomatic relief.

Drugs used for their effects on the gastrointestinal system, as to control gastric acidity, regulate gastrointestinal motility and water flow, and improve digestion.

Endogenous compounds and drugs that bind to and activate SEROTONIN RECEPTORS. Many serotonin receptor agonists are used as ANTIDEPRESSANTS; ANXIOLYTICS; and in the treatment of MIGRAINE DISORDERS.

Absorption, Distribution and Excretion · 2 Einträge

Cisapride is rapidly absorbed after oral administration, with an absolute bioavailability of 35-40%.

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.

Cellular LocationsMembrane

Verwendung und Herstellung

Uses · 2 Einträge

MEDICATION

For the symptomatic treatment of adult patients with nocturnal heartburn due to gastroesophageal reflux disease.

Formulations/PreparationsVanDaele, Eur. Pat. Appl. 76,530 (1983 to Janssen)