【医学ppt课件】Digestive System Agents
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19
Cisapride in Clinic
In 1995, it was recorded in BP and EP. In 1997, it became top 25 of 500 best-selling
drugs with 1.04 billion dollars. In 2000, 386 severe ADR, 125 death. It was suspended in USA and UK in same year.
3 and 4-substituents on the same side of pyridine ring
15
Cl
O 4O 3
N H
N
F O
H2N
O
O
O
F
Cl
N H
N
O
H2N
O
O
O
F
Cl
N H
N
O
H2N
O
O
O
F
Cl
N H
N
O
H2N
O
2-cis isomers
in clinic
4-isomers of
Structure is similar, but has no function for anti-
cardiac arrhythmias
Cl H2N
O
N N H O
metoM cetl甲 ooc氧 lo pp 普 rra 胺 amimdeide
also used as an antiemetic
11
Metoclopramide
It is an antiemetic and gastroprokinetic agent.
To treat nausea and vomiting, and to facilitate gastric emptying in patients with gastroparesis.
12
13
Cisapride
14
3 and 4-C are
Cisapride (西沙必利) both chiral C
O
F
Cl 5
1
O
43
2
N
H
N
O
4
1
H2N
2O
3
4-amino-5-chloro-N-((3S,4S)-1-[3-(4-fluoro phenoxy)propyl]-3-methoxypiperidin-4-yl)2-methoxybenzamide
It was discovered by Janssen Pharmaceutica in 1980.
18
In Clinic
Various GI dyskinesis(动力障碍)such as Gastroparesis(胃肌轻瘫)and regurgitation(反胃).
Side effect：an exceptional life-threatening ventricular arrhythmia (室性心律失常).
7
Common Prokinetics
Cl H2N
O
N N H O
Metoclopramide
H N
O
H
N
Cl
N
ห้องสมุดไป่ตู้
NO
N
Domperidone
O
F
Cl
NO
H
N
O
H2N
O
Cisapride
8
9
Prokinetics
10
Metoclopramide (甲氧氯普胺)
胃复安
H2N
O N
N H
proP c普 roa鲁 ca i卡 inna 因 am 胺 mideide
Classification
D2 receptor antagonists Metoclopramide(甲氧氯普胺)
Periphery D2 receptor antagonists Domperidone(多潘立酮) Acetylcholine agonists Cisapride(西沙必利)
Various trade names: Maxolon (Shire/Valeant), Reglan (Schwarz Pharma), Degan (Lek), Maxeran (Sanofi Aventis), Primperan (Sanofi Aventis), and Pylomid (Bosnalijek).
Chapter 5 Digestive System Agents
1
Section 3 Prokinetics
(促动力药)
4
5
6
Concept and classification
Prokinetics
Promote GI content to push forward, used in the treatment of GI dyskinesis(动力障碍) such as reflux esophagitis(返流食道炎), dyspepsia(消化不良), intestinal obstruction(肠梗阻), etc.
Cisapride
16
Metabolism of Cisapride
O
O
F
Cl
N H
N
O
H2N
O
Dealkylation
Oxidation
O
O
Cl
N H
NH
Cl
H2N
O
O
O
HO
F
N H
N
O
H2N
O
17
Cisapride in Clinic
Cisapride is a parasympathomimetic and gastroprokinetic agent that acts as a serotonin 5-HT4 receptor agonist.
Stimulation of the serotonin receptors increases acetylcholine release in the enteric nervous system.
It is sold under the trade names Prepulsid (JanssenOrtho) and Propulsid (in the U.S.).
20
New “Pride” Prokinetic Drugs
O
O N H
O
O
O
N
Itopride
O
Cl
N
N
H
O
H2N
O
Much safer
F
Mosapride
21
22
Domperidone (多潘立酮)
H N
O N
H N O N
N
5-chloro-1-(1-[3-(2-oxo-2,3-dihydro1H-benzo[d]imidazol-1-yl)propyl] piperidin-4-yl)-1H-benzo[d]imidazol2(3H)-one
Cisapride in Clinic
In 1995, it was recorded in BP and EP. In 1997, it became top 25 of 500 best-selling
drugs with 1.04 billion dollars. In 2000, 386 severe ADR, 125 death. It was suspended in USA and UK in same year.
3 and 4-substituents on the same side of pyridine ring
15
Cl
O 4O 3
N H
N
F O
H2N
O
O
O
F
Cl
N H
N
O
H2N
O
O
O
F
Cl
N H
N
O
H2N
O
O
O
F
Cl
N H
N
O
H2N
O
2-cis isomers
in clinic
4-isomers of
Structure is similar, but has no function for anti-
cardiac arrhythmias
Cl H2N
O
N N H O
metoM cetl甲 ooc氧 lo pp 普 rra 胺 amimdeide
also used as an antiemetic
11
Metoclopramide
It is an antiemetic and gastroprokinetic agent.
To treat nausea and vomiting, and to facilitate gastric emptying in patients with gastroparesis.
12
13
Cisapride
14
3 and 4-C are
Cisapride (西沙必利) both chiral C
O
F
Cl 5
1
O
43
2
N
H
N
O
4
1
H2N
2O
3
4-amino-5-chloro-N-((3S,4S)-1-[3-(4-fluoro phenoxy)propyl]-3-methoxypiperidin-4-yl)2-methoxybenzamide
It was discovered by Janssen Pharmaceutica in 1980.
18
In Clinic
Various GI dyskinesis(动力障碍)such as Gastroparesis(胃肌轻瘫)and regurgitation(反胃).
Side effect：an exceptional life-threatening ventricular arrhythmia (室性心律失常).
7
Common Prokinetics
Cl H2N
O
N N H O
Metoclopramide
H N
O
H
N
Cl
N
ห้องสมุดไป่ตู้
NO
N
Domperidone
O
F
Cl
NO
H
N
O
H2N
O
Cisapride
8
9
Prokinetics
10
Metoclopramide (甲氧氯普胺)
胃复安
H2N
O N
N H
proP c普 roa鲁 ca i卡 inna 因 am 胺 mideide
Classification
D2 receptor antagonists Metoclopramide(甲氧氯普胺)
Periphery D2 receptor antagonists Domperidone(多潘立酮) Acetylcholine agonists Cisapride(西沙必利)
Various trade names: Maxolon (Shire/Valeant), Reglan (Schwarz Pharma), Degan (Lek), Maxeran (Sanofi Aventis), Primperan (Sanofi Aventis), and Pylomid (Bosnalijek).
Chapter 5 Digestive System Agents
1
Section 3 Prokinetics
(促动力药)
4
5
6
Concept and classification
Prokinetics
Promote GI content to push forward, used in the treatment of GI dyskinesis(动力障碍) such as reflux esophagitis(返流食道炎), dyspepsia(消化不良), intestinal obstruction(肠梗阻), etc.
Cisapride
16
Metabolism of Cisapride
O
O
F
Cl
N H
N
O
H2N
O
Dealkylation
Oxidation
O
O
Cl
N H
NH
Cl
H2N
O
O
O
HO
F
N H
N
O
H2N
O
17
Cisapride in Clinic
Cisapride is a parasympathomimetic and gastroprokinetic agent that acts as a serotonin 5-HT4 receptor agonist.
Stimulation of the serotonin receptors increases acetylcholine release in the enteric nervous system.
It is sold under the trade names Prepulsid (JanssenOrtho) and Propulsid (in the U.S.).
20
New “Pride” Prokinetic Drugs
O
O N H
O
O
O
N
Itopride
O
Cl
N
N
H
O
H2N
O
Much safer
F
Mosapride
21
22
Domperidone (多潘立酮)
H N
O N
H N O N
N
5-chloro-1-(1-[3-(2-oxo-2,3-dihydro1H-benzo[d]imidazol-1-yl)propyl] piperidin-4-yl)-1H-benzo[d]imidazol2(3H)-one