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Dolcanatide (formerly SP-333; SP333; SP 333) is the second uroguanylin analog currently being developed for ulcerative colitis by Synergy Pharmaceuticals which is a biopharmaceutical company focused on the development and commercialization of novel gastrointestinal (GI) therapies. Analogs of uroguanylin, a naturally occurring human GI peptide, have the potential for the treatment of functional GI disorders and inflammatory bowel disease. Plecanatide (Trade name Trulance; formerly SP-304), a 16 amino acid peptide, is a drug approved by the FDA for the treatment of chronic idiopathic constipation (CIC) and irritable bowel syndrome with constipation. Plecanatide is an agonist of guanylate cyclase-C. It works as a laxative by drawing water into the gastrointestinal tract thereby softening stool and encouraging its natural passage. Plecanatide increases intestinal transit and fluid through a buildup of cGMP. As of January 2017, Plecanatide is approved in the United States for the treatment of chronic idiopathic constipation in adults. As of January 2017, Plecanatide is approved in the United States for the treatment of chronic idiopathic constipation in adults.
Physicochemical Properties
| Molecular Formula |
C65H104N18O26S4 |
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| Molecular Weight | 1681.88627052307 | |
| Exact Mass | 1680.625 | |
| CAS # | 1092457-65-2 | |
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| PubChem CID | 91826710 | |
| Appearance | White to off-white solid powder | |
| LogP | -8.2 | |
| Hydrogen Bond Donor Count | 23 | |
| Hydrogen Bond Acceptor Count | 31 | |
| Rotatable Bond Count | 28 | |
| Heavy Atom Count | 113 | |
| Complexity | 3490 | |
| Defined Atom Stereocenter Count | 16 | |
| SMILES | S1C[C@H]2C(N[C@H](C(N[C@@H](CC(N)=O)C(N[C@H](C(N[C@@H](C)C(N[C@H](C(N[C@H](C(NCC(N[C@H](C(N[C@@H](C(=O)O)CC(C)C)=O)CS1)=O)=O)[C@@H](C)O)=O)CSSC[C@@H](C(N[C@@H](CCC(=O)O)C(N[C@H](C(N2)=O)CC(C)C)=O)=O)NC([C@H](CCC(=O)O)NC([C@H](CC(=O)O)NC([C@@H](CC(N)=O)N)=O)=O)=O)=O)=O)C(C)C)=O)=O)C(C)C)=O |
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| InChi Key | NSPHQWLKCGGCQR-HLHYUOOASA-N | |
| InChi Code | InChI=1S/C65H104N18O26S4/c1-25(2)15-34-55(98)80-41-24-113-110-21-38(58(101)77-37(65(108)109)16-26(3)4)71-44(87)20-69-62(105)50(30(10)84)83-61(104)40(78-51(94)29(9)70-63(106)48(27(5)6)81-57(100)35(18-43(68)86)76-64(107)49(28(7)8)82-60(41)103)23-112-111-22-39(59(102)73-32(53(96)75-34)11-13-45(88)89)79-54(97)33(12-14-46(90)91)72-56(99)36(19-47(92)93)74-52(95)31(66)17-42(67)85/h25-41,48-50,84H,11-24,66H2,1-10H3,(H2,67,85)(H2,68,86)(H,69,105)(H,70,106)(H,71,87)(H,72,99)(H,73,102)(H,74,95)(H,75,96)(H,76,107)(H,77,101)(H,78,94)(H,79,97)(H,80,98)(H,81,100)(H,82,103)(H,83,104)(H,88,89)(H,90,91)(H,92,93)(H,108,109)/t29-,30+,31+,32-,33-,34-,35-,36-,37+,38-,39-,40-,41-,48-,49-,50-/m0/s1 | |
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| HS Tariff Code | 2934.99.9001 | |
| Storage |
Powder-20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
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| Shipping Condition | Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs) |
Biological Activity
| ln Vitro | In T84 cells, dolcanatide (0-10 μM; 30 minutes) increases cGMP production and GC-C receptors in a dose-dependent manner [2]. In Caco-2 and T84 cells, lipopolysaccharide-induced paracellular permeability is inhibited by dolcanatide (1 μM; 16 hours) [1]. |
| ln Vivo | Oral dolcanatide (0.01 and 0.05 mg/kg; once) decreases rectal allodynia in rats induced by TNBS [1]. Oral dolcanatide (0.01 and 0.05 mg/kg; once) decreases colorectal hypersensitivity (CRD) in rats induced by stress [1]. |
| Cell Assay |
Cell viability assay [2] Cell Types: T84 Cell Tested Concentrations: 0-10 μM Incubation Duration: 30 minutes Experimental Results: Shows EC50 value of 0.28 μM. |
| Animal Protocol |
Animal/Disease Models: TNBS-induced rectal allodynia in rats [1] Doses: 0.01 and 0.05 mg/kg Route of Administration: oral; Route of Administration: oral. 0.01 and 0.05 mg/kg; Experimental Results:Attenuated the increased number of abdominal contractions caused by TNBS (inflation pressure up to 60 mmHg). Animal/Disease Models: Wistar rat stress visceral hypersensitivity [1] Doses: 0.01 and 0.05 mg/kg 0.01 and 0.05 mg/kg; Experimental Results: As CRD (colorectal distension) pressure increases, PRS (partial restraint stress) ) caused a significant reduction in abdominal contraction rate. |
| References |
[1]. Oral treatment with plecanatide or dolcanatide attenuates visceral hypersensitivity via activation of guanylate cyclase-C in rat models. World J Gastroenterol. 2018 May 7;24(17):1888-1900. [2]. Plecanatide and dolcanatide, novel guanylate cyclase-C agonists, ameliorate gastrointestinal inflammation in experimental models of murine colitis. World J Gastrointest Pharmacol Ther. 2015 Nov 6;6(4):213-22. |
| Additional Infomation |
Dolcanatide has been investigated in Exposure. Dolcanatide is an orally administered analog of the human endogenous natriuretic hormone uroguanylin and guanylate cyclase C (GC-C) agonist, with potential laxative, anti-nociceptive and anti-inflammatory activities. Upon administration, dolcanatide, by mimicking uroguanylin, binds to and activates GC-C locally on endothelial cells in the gastrointestinal (GI) tract, without entering the systemic circulation. Activation of GC-C results in an increase in cyclic guanosine monophosphate (cGMP). Increased concentrations of cGMP lead to the activation of the anion channel cystic fibrosis transmembrane conductance regulator (CFTR). CFTR activation increases the secretion of negatively charged ions, particularly chloride and bicarbonate, into the GI tract lumen, which further drives sodium ions and then water into the lumen. This leads to increased fluid secretion in the GI tract, accelerated transit and changes in stool consistency. In addition, ion channel modulation may decrease muscle contractions and the activity of pain-sensing nerves, thereby decreasing intestinal pain. Also, GC-C may inhibit the secretion of pro-inflammatory cytokines, which may ameliorate GI inflammation. Uroguanylin, a naturally occurring human GI peptide, is a ligand for GC-C and plays a key role in anti-inflammatory processes in the GI tract. |
Solubility Data
| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples. Injection Formulations (e.g. IP/IV/IM/SC) Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] *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. Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline) Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline) Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline) Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil) Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Oral Formulations Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). Oral Formulation 3: Dissolved in PEG400 Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose Oral Formulation 6: Mixing with food powders Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 0.5946 mL | 2.9728 mL | 5.9457 mL | |
| 5 mM | 0.1189 mL | 0.5946 mL | 1.1891 mL | |
| 10 mM | 0.0595 mL | 0.2973 mL | 0.5946 mL |