| Size | Price | Stock | Qty |
|---|---|---|---|
| 1mg |
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| 5mg |
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| 10mg |
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| Other Sizes |
| Targets |
Guanylate cyclase-C; linaclotide metabolite
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|---|---|
| ln Vitro |
High-affinity binding of MM 419447 to T84 cells causes a notable intracellular buildup of cyclic guanosine-39,59-monophosphate (cGMP) in a concentration-dependent manner[1].
|
| ln Vivo |
The Cmax, AUC0-6, and t1/2 values for MM 419447 (10 mg/kg; po) dosing are 27 ng/mL, < 29.7 ng h/mL, and 0.33 hours, respectively[1].
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| Animal Protocol |
Animal/Disease Models: Female SD (Sprague-Dawley) rats[1]
Doses: 10 mg/kg Route of Administration: Po (pharmacokinetic/PK Analysis) Experimental Results: The Cmax, AUC0-6 and Tmax were 27 ng/mL, ≤ 29.7 ng h/mL and 0.33 hrs (hours), respectively. |
| References | |
| Additional Infomation |
Linaclotide is a potent guanylate cyclase C agonist and a therapeutic peptide approved in the United States for the treatment of constipation-predominant irritable bowel syndrome and chronic idiopathic constipation. We report for the first time the metabolism, degradation, and distribution of linaclotide in animals and humans. We investigated the metabolic stability of linaclotide under simulated gastrointestinal conditions and identified its metabolite MM-419447 (CCEYCCNPACTGC), a key component for the pharmacological action of linaclotide. Systemic exposure to these bioactive peptides was low in rats and humans; both systemic and portal vein concentrations of linaclotide and MM-419447 were observed in rats, confirming minimal absorption of these two peptides after oral administration. Linaclotide is stable in the acidic environment of the stomach and is converted to MM-419447 in the small intestine. The disulfide bonds of both peptides are reduced in the small intestine, followed by proteolytic degradation. After oral administration of linaclotide, the amount of active peptide excreted in rat feces was less than 1%, while the average amount excreted in human feces was 3-5%; in both cases, MM-419447 was the major peptide recovered. MM-419447 binds to T84 cells with high affinity in vitro, leading to a significant concentration-dependent accumulation of intracellular cyclic guanosine monophosphate (cGMP). In a rat gastrointestinal function model, oral administration of MM-419447 significantly increased fluid secretion in the small intestinal loop, increased cGMP levels in the intestinal lumen, and led to a dose-dependent acceleration of gastrointestinal transit. These results indicate that the active metabolite plays an important role in the pharmacological effects of linaclotide. [1]
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| Molecular Formula |
C50H70N14O19S6
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|---|---|
| Molecular Weight |
1363.56
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| Exact Mass |
1362.326
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| CAS # |
1092457-78-7
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| PubChem CID |
156613899
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| Sequence |
H-Cys(1)-Cys(2)-Glu-Tyr-Cys(3)-Cys(1)-Asn-Pro-Ala-Cys(2)-Thr-Gly-Cys(3)-OH
CCEYCCNPACTGC (Disulfide bridge:Cys1-Cys6; Cys2-Cys10; Cys5-Cys13) L-cysteinyl-L-cysteinyl-L-alpha-glutamyl-L-tyrosyl-L-cysteinyl-L-cysteinyl-L-asparagyl-L-prolyl-L-alanyl-L-cysteinyl-L-threonyl-glycyl-L-cysteine (1->6),(2->10),(5->13)-tris(disulfide) |
| SequenceShortening |
CCEYCCNPACTGC
H-C(1)C(2)EYC(3)C(1)NPAC(2)TGC(3)-OH |
| Appearance |
White to off-white solid powder
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| LogP |
-7.8
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| Hydrogen Bond Donor Count |
17
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| Hydrogen Bond Acceptor Count |
26
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| Rotatable Bond Count |
9
|
| Heavy Atom Count |
89
|
| Complexity |
2650
|
| Defined Atom Stereocenter Count |
13
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| SMILES |
O=C1[C@@H](NC([C@]2([H])CSSC[C@@H](C(N[C@]3([H])C(N[C@@H](C(N[C@H](C(N[C@@]([H])(CSSC[C@H](NC(CNC(C(NC([C@]([H])(CSSC3)NC([C@@H](NC([C@]3([H])CCCN31)=O)C)=O)=O)[C@H](O)C)=O)=O)C(=O)O)C(N2)=O)=O)CC1C=CC(=CC=1)O)=O)CCC(=O)O)=O)=O)N)=O)CC(=O)N
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| InChi Key |
PEHXAHVIVOAJQN-BRJMRMHMSA-N
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| InChi Code |
InChI=1S/C50H70N14O19S6/c1-21-39(71)59-32-19-87-86-16-29-43(75)56-26(9-10-37(69)70)41(73)57-27(12-23-5-7-24(66)8-6-23)42(74)61-31(18-88-89-20-33(50(82)83)55-36(68)14-53-48(80)38(22(2)65)63-46(32)78)45(77)62-30(17-85-84-15-25(51)40(72)60-29)44(76)58-28(13-35(52)67)49(81)64-11-3-4-34(64)47(79)54-21/h5-8,21-22,25-34,38,65-66H,3-4,9-20,51H2,1-2H3,(H2,52,67)(H,53,80)(H,54,79)(H,55,68)(H,56,75)(H,57,73)(H,58,76)(H,59,71)(H,60,72)(H,61,74)(H,62,77)(H,63,78)(H,69,70)(H,82,83)/t21-,22+,25-,26-,27-,28-,29-,30-,31-,32-,33-,34-,38-/m0/s1
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| Chemical Name |
(1R,4S,7S,13S,16R,21R,24R,27S,30S,33R,38R,44S)-21-amino-13-(2-amino-2-oxoethyl)-27-(2-carboxyethyl)-44-[(1R)-1-hydroxyethyl]-30-[(4-hydroxyphenyl)methyl]-4-methyl-3,6,12,15,22,25,28,31,40,43,46,51-dodecaoxo-18,19,35,36,48,49-hexathia-2,5,11,14,23,26,29,32,39,42,45,52-dodecazatetracyclo[22.22.4.216,33.07,11]dopentacontane-38-carboxylic acid
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| Synonyms |
MM 419447; 1092457-78-7; MM-419447; SCHEMBL24483647; MM419447; (1R,4S,7S,13S,16R,21R,24R,27S,30S,33R,38R,44S)-21-amino-13-(2-amino-2-oxoethyl)-27-(2-carboxyethyl)-44-[(1R)-1-hydroxyethyl]-30-[(4-hydroxyphenyl)methyl]-4-methyl-3,6,12,15,22,25,28,31,40,43,46,51-dodecaoxo-18,19,35,36,48,49-hexathia-2,5,11,14,23,26,29,32,39,42,45,52-dodecazatetracyclo[22.22.4.216,33.07,11]dopentacontane-38-carboxylic acid
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month Note: Please store this product in a sealed and protected environment, avoid exposure to moisture. |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO: 100 mg/mL (73.34 mM)
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|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (1.83 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. Solubility in Formulation 2: ≥ 2.5 mg/mL (1.83 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 0.7334 mL | 3.6669 mL | 7.3337 mL | |
| 5 mM | 0.1467 mL | 0.7334 mL | 1.4667 mL | |
| 10 mM | 0.0733 mL | 0.3667 mL | 0.7334 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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