| Size | Price | Stock | Qty |
|---|---|---|---|
| 1mg |
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| 100mg | |||
| Other Sizes |
| Targets |
Tryptophan hydroxylase (TPH1/TPH2)
TPH1 (tryptophan hydroxylase 1) and TPH2 (tryptophan hydroxylase 2). TPH1 is primarily expressed in peripheral tissues (especially the gut), while TPH2 is predominantly expressed in the brain and central nervous system. Rodatristat inhibits both isoforms with high potency. |
|---|---|
| ln Vitro |
As a follow-up to the discovery of our spirocyclic proline-based TPH1 inhibitor lead, we describe the optimization of this scaffold. Through a combination of X-ray co-crystal structure guided design and an in vivo screen, new substitutions in the lipophilic region of the inhibitors were identified. [1]
Rodatristat inhibits TPH1 with an IC50 of 33 nM and TPH2 with an IC50 of 7 nM. It shows higher potency against TPH2 compared to TPH1. The compound significantly reduces serotonin (5-HT) levels in the mouse intestine. Detailed in vitro activity against additional targets has not been extensively reported. |
| ln Vivo |
Rodatristat (10-50 mg/kg; oral; mice) treatment decreased intestinal 5-HT concentrations at 50 mg/kg and was much less effective at the lower dose of 10 mg/kg [1].
Rodatristat (10-50 mg/kg; p.o.; mice) treatment reduces intestinal 5-HT concentrations at 50 mg/kg. Its efficacy drops off significantly at the lower 10 mg/kg dose. The compound demonstrates robust reduction of intestinal serotonin levels in mice. Further in vivo studies would be needed to fully characterize its pharmacodynamic profile. |
| Enzyme Assay |
TPH enzyme activity assay: Recombinant human TPH1 or TPH2 is incubated with varying concentrations of Rodatristat, 100 µM L-tryptophan, 100 µM 6-methyl-5,6,7,8-tetrahydropterin (6-MPH₄), 1 mM DTT, and catalase in assay buffer (50 mM HEPES pH 7.0, 100 mM NaCl) at 37°C for 30-60 min. The reaction is terminated by adding perchloric acid. The product 5-hydroxytryptophan (5-HTP) is quantified by HPLC with fluorescence detection. IC50 values are calculated from dose-response curves.
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| Cell Assay |
Serotonin depletion assay in cultured cells: Cells expressing TPH1 (e.g., human intestinal cell lines) are treated with Rodatristat at varying concentrations (1 nM - 10 µM) for 24-48 hours. Culture medium and cell lysates are collected. Serotonin (5-HT) levels are measured by ELISA or HPLC with electrochemical detection. The concentration-dependent reduction of 5-HT levels is calculated, and EC50 values are determined.
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| Animal Protocol |
Animal/Disease Models: Mice[1]
Doses: 10 mg/kg and 50 mg/kg Route of Administration: Oral Experimental Results:Intestinal 5-HT concentration diminished at the 50 mg/kg dose, and its efficacy was significant at the 10 mg/kg dose decline. Mouse intestinal serotonin reduction model: Mice are administered Rodatristat via oral gavage at doses of 10, 25, or 50 mg/kg. After a specified time (typically 4-24 hours), animals are euthanized and intestinal tissues are collected. Tissue homogenates are prepared and serotonin (5-HT) levels are measured by ELISA or HPLC. The percentage reduction in intestinal 5-HT levels compared to vehicle-treated controls is calculated. |
| ADME/Pharmacokinetics |
No detailed pharmacokinetic data has been published in the available literature. Rodatristat has a molecular weight of 561.98 g/mol and molecular formula C₂₇H₂₇ClF₃N₅O₃. It is administered orally in mice. Comprehensive PK parameters such as bioavailability, half-life, and plasma protein binding remain to be characterized.
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| Toxicity/Toxicokinetics |
No detailed toxicity data has been published in the available literature. Rodatristat is for research use only and not for human therapeutic applications. Standard laboratory safety practices should be followed when handling this compound. As a TPH inhibitor, potential effects on serotonin levels in various tissues should be considered.
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| References | |
| Additional Infomation |
Rodatristat (KAR5417) is a potent dual inhibitor of TPH1 and TPH2, the rate-limiting enzymes in serotonin biosynthesis. It shows IC50 values of 33 nM for TPH1 and 7 nM for TPH2. Rodatristat significantly reduces intestinal serotonin levels in mice. It is a research compound for studying serotonin biology and related disorders. No clinical trials or approved上市 status have been reported.
|
| Molecular Formula |
C27H27CLF3N5O3
|
|---|---|
| Molecular Weight |
561.983195543289
|
| CAS # |
1673568-73-4
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| Related CAS # |
1673568-73-4;1673571-51-1 (ethyl);
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| PubChem CID |
117947705
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| Appearance |
White to off-white solid powder
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| Hydrogen Bond Donor Count |
3
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| Hydrogen Bond Acceptor Count |
11
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| Rotatable Bond Count |
6
|
| Heavy Atom Count |
39
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| Complexity |
840
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| Defined Atom Stereocenter Count |
2
|
| SMILES |
C1CN(CCC12C[C@H](NC2)C(=O)O)C3=CC(=NC(=N3)N)O[C@H](C4=C(C=C(C=C4)Cl)C5=CC=CC=C5)C(F)(F)F
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| Synonyms |
KAR5417; KAR 5417; KAR-5417
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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 |
| 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) |
May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples
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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
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *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). View More
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)] 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). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.7794 mL | 8.8971 mL | 17.7942 mL | |
| 5 mM | 0.3559 mL | 1.7794 mL | 3.5588 mL | |
| 10 mM | 0.1779 mL | 0.8897 mL | 1.7794 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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