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Plecanatide Powder is a highly pure synthetic peptide active pharmaceutical ingredient (API) with a structure similar to the human guanylate cyclase-C (GC-C) agonist uridine. It is used to treat chronic idiopathic constipation (CIC) and irritable bowel syndrome with constipation (IBS-C). In its powder form, it is typically a white to off-white lyophilized powder and needs to be stored at low temperatures (2-8°C) in the dark to maintain stability.
Plecanatide activates the intestinal GC-C receptor, increases intracellular cGMP, stimulates intestinal fluid secretion and accelerates intestinal peristalsis. Its powder formulation is convenient for precisely preparing oral preparations (such as capsules), and has an extremely low bioavailability (<0.1%), mainly acting locally in the intestine, with a low risk of systemic exposure.
Key advantages include:
pH sensitivity: Activated in the acidic environment of the duodenum, reducing degradation in the stomach;
Low-dose high-efficiency (3mg per day)
Safety: There is no known potential for abuse. Common side effects are only mild diarrhea.
Currently, it is only for legal medical and scientific research purposes and must be handled in accordance with GMP standards.
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Customized Bottle Caps And Corks:
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Chemical Formula |
C65H104N18O26S4 |
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Exact Mass |
1681 |
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Molecular Weight |
1682 |
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m/z |
1681 (100.0%), 1682 (70.3%), 1683 (24.3%), 1683 (18.1%), 1684 (12.7%), 1682 (6.6%), 1684 (5.5%), 1683 (5.3%), 1683 (4.7%), 1685 (4.4%), 1684 (3.8%), 1682 (3.2%), 1683 (2.3%), 1684 (1.6%), 1685 (1.3%), 1685 (1.2%), 1684 (1.2%), 1682 (1.2%)C, 46.42; H, 6.23; N, 14.99; O, 24.73; S, 7.62 |
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Elemental Analysis |
C, 46.42; H, 6.23; N, 14.99; O, 24.73; S, 7.62 |
Core Mechanism: Precise Regulation Targeting the Gut GC-C Receptor
Plecanatide is a cyclic polypeptide composed of 16 amino acids. As a selective agonist of the guanylate cyclase-C (GC-C) receptor, its action pathway is highly targeted to the gut:
Receptor activation: By binding to the GC-C receptor on the surface of intestinal epithelial cells, it catalyzes the synthesis of intracellular cyclic guanosine monophosphate (cGMP), with an EC50 value of 190 nM (T84 cell experiment), indicating high affinity.
Ion channel regulation: An increase in cGMP concentration activates the cystic fibrosis transmembrane conductance regulator (CFTR), promoting the secretion of chloride ions (Cl⁻) and bicarbonate ions (HCO₃⁻) into the intestinal lumen, while also driving passive transport of sodium ions (Na⁺) and water through osmosis, increasing the volume of intestinal fluid.
Gastrointestinal motility improvement: Increased fluid secretion directly softens feces and enhances peristaltic reflexes by stimulating mechanical receptors in the intestinal wall, accelerating the transfer of contents.
Clinical application: First-line treatment for chronic idiopathic constipation (CIC)
Indications and dosage instructions
Approval Authority: The US FDA (in 2017) and the EU EMA (in 2018) approved for the treatment of adult CIC.
Recommended Dose: Once daily, 3 mg orally, swallow the tablet whole or mix it with water before taking.
Special Populations:
Children under 6 years old are prohibited from using (safety has not been established);
Pregnant women and lactating women should use with caution (animal experiments show no teratogenicity at high doses, but human data is limited).
Efficacy Evidence
Phase III clinical trial:
Study design: 6,125 patients with CIC were included and divided into 2-3 phases (951 cases) and phase 3 (5,174 cases), with comparison between Plecanatide and placebo.
Key results:
The proportion of patients with an increase of ≥1 times per week in the number of completely spontaneous defecations (CSBMs) reached 62.9% (vs 34.6% with placebo);
The defecation frequency was significantly improved (p < 0.001), and no acute diarrhea was caused (the incidence of severe diarrhea was < 1%).
Long-term safety: 2-year animal carcinogenicity studies (90 mg/kg/d for mice, 100 mg/kg/d for rats) did not detect an increased risk of tumors, and the long-term exposure data for humans support its safety.
Advantages over traditional laxatives
Permeability laxatives (such as polyethylene glycol): They take effect quickly (within 12-24 hours), but long-term use can lead to electrolyte imbalance (such as hyponatremia) and have a low patient compliance (requiring a large amount of water intake).
Stimulant laxatives (such as bisacodyl): They take effect the fastest (within 6-12 hours), but long-term use may cause intestinal neuropathy, leading to "laxative-induced enteropathy".
Plecanatide: It takes effect moderately (within 24-48 hours), has a diarrhea incidence rate of less than 5%, and has no risk of electrolyte imbalance, making it suitable for long-term use.
Frontier Exploration: Potential Applications of Inflammatory Bowel Disease (IBD)
Anti-inflammatory Mechanism
Animal model validation: In the mouse colitis model induced by dextran sulfate sodium (DSS), Plecanatide (0.5 - 2.5 mg/kg/d orally) significantly reduced the disease activity index (DAI), decreased colonic shortening and mucosal ulcers.
Action pathway:
By activating the GC-C receptor and inhibiting the NF-κB signaling pathway, it reduces the release of pro-inflammatory factors (IL-6, TNF-α);
Enhances intestinal barrier function and reduces the risk of bacterial translocation.
Clinical translation challenges
Dose optimization: IBD patients require higher doses (5 - 10 mg/d) to overcome the downregulation of receptor expression caused by intestinal inflammation.
Combination therapy: Combining with 5-ASA drugs or biological agents may enhance the therapeutic effect, but the pharmacokinetic interactions need to be further verified.
Formulation optimization: Clinical value of powder formulation
Solubility and stability
Solubility: 100 mg/mL (59.46 mM) in DMSO, requires ultrasonic assistance for dissolution; Hygroscopicity of DMSO may affect stability, it is recommended to use freshly opened solvent.
Storage conditions: Powder form -20℃ for 1 year; After preparing into solution, it needs to be aliquoted and stored at -80℃ (use within 6 months).
Flexibility of administration
Dose adjustment: The powder formulation can be precisely weighed, suitable for individualized dosing for children or patients with impaired liver or kidney function.
Combination therapy: It can be mixed with probiotic powder and achieve targeted release through enteric-coated capsules, reducing degradation by gastric acid.
Safety and Monitoring
Common adverse reactions
Diarrhea (occurrence rate < 5%): Usually mild and reversible upon discontinuation of the medication.
Headache (2% - 3%): May be related to the low permeability of the blood-brain barrier (animal experiments show extremely low exposure to the central nervous system).
Contraindications
Mechanical intestinal obstruction: Activation of the GC-C receptor may aggravate intestinal obstruction.
For pediatric patients: Prohibited for children under 6 years old (potential risk of dehydration).
A preparation method for plecanatide powder, characterized in that it comprises the following steps:
S1. Coupling fmoc leu oh with wangresin to obtain fmoc leu wangresin, followed by the peptide sequence from the c-terminus to the n-terminus of the main chain of procanapeptide, and using propyl phosphonic anhydride (t3p) as a condensation agent to obtain procanapeptide 7-16 fully protective peptide resin; Fmoc leu oh was coupled with 2-ctcresin to prepare fmoc leu ctresin. Following the peptide sequence from the c-terminus to the n-terminus of the main chain of procaine, procaine 1-6 fully protected peptide resin was obtained using t-3p as the condensation agent;
S2. Perform full protective cleavage on the 1-6 full protective peptide resin of Pukanatide, connect it with the 7-16 full protective peptide resin of Pukanatide to obtain the Pukanatide resin, and cleavage to obtain linear Pukanatide;
S3. Cyclize linear procanapeptide to obtain procanapeptide monocyclic peptide;
S4. Purify the Pukanatide monocyclic peptide, perform secondary cyclization on the purified Pukanatide monocyclic peptide to obtain Pukanatide bicyclic peptide, and purify it;
S5. Wash and concentrate the purified Pukanatide bicyclic peptide to obtain the Pukanatide.
Its characteristics are:
In step s1, sequentially couple fmoc cys (r1) - oh, fmoc gly-oh, fmoc thr (otbu) - oh, fmoc cys (r2) - oh, fmoc ala oh, fmoc val oh, fmoc asn (trt) - oh, fmoc val oh, fmoc cys (r1) - oh to fmoc leu wangresin to obtain the fully protective peptide resin of procanapeptide 7-16; Sequentially coupling fmoc glu (otbu) - oh, fmoc cys (r2) - oh, fmoc glu (otbu) - oh, fmoc asps (otbu) - oh, boc asn (trt) - oh onto fmoc leu ctresin to obtain the fully protective peptide resin 1-6 of the procanapeptide; Among them, r1 and r2 are independently selected from trt, acm, mmt or tbu protective groups, and r1 and r2 are different.
In step s2, using propyl phosphate anhydride as a condensation agent, connect the fully protective peptide 1-6 of Pukanatide with the fully protective peptide resin 7-16 of Pukanatide. In step s2, the lysis solution used for the cleavage of the fully protective peptide is prepared by mixing trifluoroethanol and dichloromethane in a volume ratio of 1:3-5; The lysis solution of peptide resin includes 90-95% TFA, as well as one or more of 1-5% triisopropylsilane, 1-5% EDT, 1-5% water, and 1-5% phenol.
In step s3, hydrogen peroxide is used as the cyclization solution to obtain a single cyclic peptide of procanatide.
In step s4, sepax polyrp was used as the filler, 1-5 ‰ trifluoroacetic acid was used as the mobile phase a, and acetonitrile was used as the mobile phase b to purify the procanapeptide monocyclic peptide. The method according to claim 1, characterized in that in step s4, iodine solution is added to the procarnatide monocyclic peptide for secondary cyclization. In step s4, the purification of the procaine bicyclic peptide involves two purification processes: using sepapolyrp as the filler, 1-5 ‰ trifluoroacetic acid as the mobile phase a, acetonitrile as the mobile phase b for primary purification, using c18 as the filler, 1-5% triethylamine and 0.1-1% phosphoric acid to prepare a mixed solution with a pH of 7-8 as the mobile phase a, and acetonitrile as the mobile phase b for secondary purification.
In step s5, the purified Pukanatide bicyclic peptide is loaded onto a Sepaxpolyrp packed column, and the tea salt in the second pure sample solution is sequentially replaced by ammonium acetate buffer equilibrium. The replaced ammonium acetate salt is removed by deionized water equilibrium, and eluted with a 90% ethanol aqueous solution. In step s5, methyl tert butyl ether is used for sedimentation.
Frequently Asked Questions
What is the function of plecanatide?
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Plecanatide is used to treat chronic idiopathic constipation (CIC) and irritable bowel syndrome with constipation (IBS-C). It works by increasing the fluid secretion of the bowels, which helps ease the passage of stools and relieve the symptoms of constipation.
Is plecanatide FDA approved?
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Plecanatide is approved by the US Food and Drug Administration (FDA) for the treatment of adults with CIC or IBS-C. Ahmed and colleagues reported on the results of a systemic review and meta-analysis that focused on the efficacy and safety of plecanatide in the treatment of these 2 conditions.
When is the best time to take plecanatide?
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Trulance can be taken any time of the day, with or without food. You shouldn't have to plan your day around your medication.
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