| Candidate ID: | R0394 |
| Source ID: | DB01079 |
| Source Type: | approved; investigational; withdrawn |
| Compound Type: |
small molecule
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| Compound Name: |
Tegaserod
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| Synonyms: |
1-(((5-Methoxyindol-3-yl)methylene)amino)-3-pentylguanidine
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| Molecular Formula: |
C16H23N5O
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| SMILES: |
CCCCCNC(=N)N\N=C\C1=CNC2=C1C=C(OC)C=C2
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| Structure: |
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| DrugBank Description: |
Novartis' brand name Zelnorm (tegaserod) had originally received approval from the US FDA in 2002 for the treatment of irritable bowel syndrome with constipation (IBS-C). It was, however, voluntarily withdrawn from widespread use in the US market in 2007 after concerns arose over the possibility that tegaserod could potentially cause dangerous cardiovascular events in patients. Since then, closer evaluations of the original data suggesting such cardiovascular risk have resulted in the limited reintroduction or 're-approval' of tegaserod for treatment of IBS-C specifically in female patients less than 65 years of age and whom are considered to be at a lower risk of a cardiovascular event than the broader population. Zelnorm (tegaserod) by Sloan Pharma subsequently gained re-approval in April of 2019. Nevertheless, tegaserod remains un-approved in certain regions.
Despite the relative complications involved in its history of regulatory approval, ever since its first introduction in 2002 tegaserod remains the only therapy for IBS-C that possesses the unique mechanism of action of acting on serotonin-4 (5-HT(4)) receptors in smooth muscle cells and in the gastrointestinal wall to facilitate actions like esophageal relaxation, peristaltic gut movement, and natural secretions in the gut, among others.
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| CAS Number: |
145158-71-0
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| Molecular Weight: |
301.394
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| DrugBank Indication: |
Tegaserod is a serotonin-4 (5-HT4) receptor agonist indicated for the treatment of adult women less than 65 years of age with irritable bowel syndrome with constipation (IBS-C) . The safety and effectiveness of tegaserod in men with IBS-C have not been established .
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| DrugBank Pharmacology: |
In general, it has been determined that tegaserod is an agonist of serotonin type-4 (5-HT(4)) receptors, an antagonist at 5-HT(2B) receptors, but is expected to possess minimal binding to 5-HT(1) receptors, and virtually no affinity for 5-HT(3) or dopamine receptors .
In clinical trials with tegaserod, centrally analyzed ECGs were recorded in 4,605 male and female patients receiving tegaserod 6 mg twice daily or placebo for IBS-C and other related motility disorders . No subject receiving the agent had an absolute QTcF above 480 ms . An increase in QTcF of 30 to 60 ms was observed in 7% of patients receiving tegaserod and 8% receiving placebo . An increase in QTcF of greater than 60 ms was observed in 0.3% and 0.2% of subjects, respectively . The effects of tegaserod on the QTcF interval were ultimately not considered to be clinically meaningful .
Furthermore, it was determined that there is a potential for tegaserod and its main metabolite (the M29 metabolite) to increase platelet aggregation in vitro . In one in vitro study, at concentrations up to 10-times the maximum plasma concentration (Cmax) at the recommended dose, tegaserod significantly increased platelet aggregation in a concentration-dependent manner up to 74% (range 11% to 74%) compared to a control vehicle (with potentiation by various agonists) . In another in vitro study, the M29 metabolite, at concentrations up to 0.6-times the Cmax of M29 also showed a 5% to 16% increase in platelet aggregation compared to the control vehicle . The clinical implications of these in vitro platelet aggregation results remain unclear .
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| DrugBank MoA: |
Irritable bowel syndrome (IBS) is a complex functional disorder comprised of various abnormal and discomforting effects on the gastrointestinal tract and bowel function . Although the cause of IBS has yet to be formally elucidated, patient experience has demonstrated that the disorder is typically associated with abdominal pain, abdominal distension, cramping or bloating, variations in urgency for bowel movements, feelings of incomplete evacuation, gastroesophageal reflux, and various other effects . In particular, IBS that features constipation as a predominant effect is categorized as constipation-predominant IBS, or IBS-C .
Concurrently, 5-Hydroxytryptamine (5-HT, or serotonin) has demonstrated the ability to elicit significant regulatory actions on gastrointestinal motility . Specifically, it has been shown that the activation of 5-HT(4) receptors located on motor neurons and interneurons in the gastrointestinal wall can cause the release of acetylcholine, substance P, and calcitonin gene-related peptide that can all facilitate the propulsion of material through the gut . Moreover, when 5-HT(4) receptors located in smooth muscle cells are also activated, activities that may alleviate symptoms of IBS-C like esophageal relaxation and the inhibition of human colonic circular muscle contraction can also occur . Additionally, activating 5-HT(4) on enteric neurons and enterocytes also cause natural fluid secretion in the gut - an action which also strongly assists in promoting the movement of content along the gastrointestinal tract .
Alternatively, it has also been observed that 5-HT may participate in generating visceral hyperalgesia in IBS, an observation supported in part by the finding of increased amounts of 5-HT and its metabolites in the plasma of patients experiencing IBS It has therefore also been proposed that antagonism of 5-HT(2B) receptors can lead to inhibition of both 5-HT mediated gastrointestinal motility and visceral hypersensitivity .
Subsequently, because tegaserod is considered to be an agonist of the 5-HT(4) receptor and an antagonist of the 5-HT(2B) receptor at clinically relevant levels, it is believed that tegaserod may elicit its mechanism of action by facilitating activities associated with the activation and antagonism of the 5-HT(4) and 5-HT(2B) receptors, like stimulating peristaltic gastrointestinal reflexes and intestinal secretion, inhibiting visceral sensitivity, enhancing basal motor activity, and normalizing impaired motility throughout the gastrointestinal tract, among other actions .
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| Targets: |
5-hydroxytryptamine receptor 4 antagonist&partial agonist; 5-hydroxytryptamine receptor 2B antagonist; 5-hydroxytryptamine receptor 2C antagonist; 5-hydroxytryptamine receptor 2A antagonist
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| Inclusion Criteria: |
Therapeutic strategy associated
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