| Size | Price | Stock | Qty |
|---|---|---|---|
| 1mg |
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| 5mg | |||
| Other Sizes |
| Targets |
5-HT1 Receptor TPH1
Tryptophan hydroxylase 1 (TPH1) [HSA:7166] [KO:K00502] (inhibitor) |
|---|---|
| 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 ethyl is a first-in-class, orally bioactive tryptophan hydroxylase 1 (TPH1) inhibitor with nanomolar in vitro potency. It selectively targets TPH1, the isoform primarily expressed in the gut, thereby reducing the biosynthesis of serotonin (5-hydroxytryptamine, 5-HT) in peripheral tissues. Unlike non-selective serotonin inhibitors, it has minimal effect on central TPH2. |
| ln Vivo |
Treatment with rodatristat ethyl (100 or 200 mg/kg; oral administration; once daily; 28 days; male Sprague-Dawley rats) significantly lowers pulmonary arterial pressure, pulmonary vessel wall thickness, and occlusion in male rats with monocrotaline (MCT) and decreases erum, gut, and lung 5-HT levels in a dose-dependent manner[1].
Rodatristat ethyl significantly reduces 5-hydroxytryptamine (5-HT) levels and effectively decreases pulmonary arterial hypertension (PAH) at low concentrations. In preclinical models, the reduction in peripheral 5-HT levels leads to a decrease in pulmonary artery pressure and reversal of vascular remodeling, providing a disease-modifying approach to PAH treatment. |
| Enzyme Assay |
For in vitro enzyme inhibition assays, recombinant human TPH1 enzyme is incubated with its substrate tryptophan and cofactors (tetrahydrobiopterin, Fe2+, and DTT) in a reaction buffer. Rodatristat ethyl is added at varying concentrations (ranging from pM to uM). The reaction proceeds for 30-60 minutes at 37degC. The production of 5-hydroxytryptophan (5-HTP) or the oxidized cofactor is measured fluorometrically (excitation ~300 nm, emission ~330 nm) or by HPLC with fluorescence detection. The IC50 (nanomolar range) is determined by plotting inhibitor concentration versus enzyme activity. Non-specific inhibition is assessed by including a TPH2 counter-screen.
|
| Cell Assay |
Cellular target engagement assays are performed using EC cells (e.g., RBL-2H3 or P815 cells, which express TPH1) or primary enterochromaffin cells. Cells are seeded in 96-well plates and treated with serial dilutions of Rodatristat ethyl (1 nM to 10 uM) for 4-24 hours. Cell culture supernatants are collected, and 5-HT levels are measured by ELISA or HPLC-ECD. Intracellular 5-HT can also be measured after cell lysis. The EC50 for reducing cellular 5-HT levels is determined. A reduction in serotonin (5-HT) level is the primary pharmacodynamic readout. Standard cytotoxicity assays (e.g., MTT or CellTiter-Glo) are performed in parallel to ensure that the reduction in 5-HT is not due to general cell death.
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| Animal Protocol |
Animal/Disease Models: Male SD (Sprague-Dawley) rats (175-200 g)[1]
Doses: 100 mg/kg or 200 mg/kg Route of Administration: Oral administration; one time/day; for 28 days Experimental Results: diminished serum, gut and lung 5-HT levels in a dose-dependent manner and Dramatically decreased pulmonary arterial pressure, and pulmonary vessel wall thickness and occlusion in male rats. In vivo efficacy studies are typically conducted in the monocrotaline (MCT) rat model or the Sugen 5416/hypoxia mouse model of PAH. Rodatristat ethyl is suspended in 0.5% methylcellulose or similar vehicle and administered once or twice daily by oral gavage at doses ranging from 3 to 100 mg/kg. Treatment begins on day 1 and continues for 2-4 weeks. Endpoints include: (1) Hemodynamic measurements: right ventricular systolic pressure (RVSP) via a pressure catheter; (2) Cardiac remodeling: right ventricular hypertrophy index (ratio of right ventricle to left ventricle plus septum, RV/(LV+S)); (3) Vascular remodeling: assessment of pulmonary artery medial wall thickness and muscularization of distal arterioles (histological analysis of lung sections stained with hematoxylin and eosin and elastic van Gieson); (4) Plasma and lung tissue levels of 5-HT (measured by ELISA or HPLC-ECD). Reduction in pulmonary arterial pressure and reversal of vascular remodeling are the primary efficacy endpoints. |
| ADME/Pharmacokinetics |
Rodatristat ethyl is an oral drug candidate. In preclinical species, it demonstrates good oral bioavailability, with significant exposure in plasma and lung tissue, the target organ for PAH. The compound is metabolized to its active parent form. Detailed clinical PK data (t1/2, Cmax, AUC, CL, Vd) are proprietary and available in clinical trial disclosures (NCT NCT03880357 in PAH patients). The pharmacokinetic profile supports once or twice daily oral dosing.
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| Toxicity/Toxicokinetics |
Standard toxicology studies have been conducted to support clinical trials, including safety pharmacology (hERG, CNS, respiratory), 28-day and 90-day repeat-dose toxicology in rodents and non-rodents (typically rats and dogs), and genetic toxicology (Ames test, chromosome aberration). As a TPH1 inhibitor, non-clinical toxicities are generally mild and may include gastrointestinal effects due to modulation of serotonin in the gut. The selective mechanism avoids central serotonergic toxicity.
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| References | |
| Additional Infomation |
See also: Rodatristat (note moved to).
Rodatristat ethyl is an investigational drug candidate that has been evaluated in clinical trials (e.g., Phase 2, NCT03880357) for the treatment of pulmonary arterial hypertension (PAH). By inhibiting peripheral serotonin synthesis via TPH1 inhibition, it represents a novel approach distinct from vasodilators. PAH is a progressive disease characterized by elevated pulmonary artery pressure leading to heart failure. As of late 2023/2024, development and regulatory status (e.g., approved or discontinued) are subject to change and are not covered in this summary. This compound is a first-in-class drug, and its development status must be checked on clinicaltrials.gov for the most current information. |
| Molecular Formula |
C29H31CLF3N5O3
|
|---|---|
| Molecular Weight |
590.036356210709
|
| Exact Mass |
589.21
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| Elemental Analysis |
C, 59.03; H, 5.30; Cl, 6.01; F, 9.66; N, 11.87; O, 8.13
|
| CAS # |
1673571-51-1
|
| PubChem CID |
92045025
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| Appearance |
Typically exists as White to off-white solids at room temperature
|
| LogP |
6.1
|
| Hydrogen Bond Donor Count |
2
|
| Hydrogen Bond Acceptor Count |
11
|
| Rotatable Bond Count |
8
|
| Heavy Atom Count |
41
|
| Complexity |
871
|
| Defined Atom Stereocenter Count |
2
|
| SMILES |
CCOC(=O)[C@@H]1CC2(CCN(CC2)C3=CC(=NC(=N3)N)O[C@H](C4=C(C=C(C=C4)Cl)C5=CC=CC=C5)C(F)(F)F)CN1
|
| InChi Key |
TZSZZENYCISATO-WIOPSUGQSA-N
|
| InChi Code |
InChI=1S/C29H31ClF3N5O3/c1-2-40-26(39)22-16-28(17-35-22)10-12-38(13-11-28)23-15-24(37-27(34)36-23)41-25(29(31,32)33)20-9-8-19(30)14-21(20)18-6-4-3-5-7-18/h3-9,14-15,22,25,35H,2,10-13,16-17H2,1H3,(H2,34,36,37)/t22-,25+/m0/s1
|
| Chemical Name |
ethyl (3S)-8-[2-amino-6-[(1R)-1-(4-chloro-2-phenylphenyl)-2,2,2-trifluoroethoxy]pyrimidin-4-yl]-2,8-diazaspiro[4.5]decane-3-carboxylate
|
| Synonyms |
KAR5585; KAR-5585; Rodatristat ethyl [USAN]; 507FY6OL37; 2,8-Diazaspiro(4.5)decane-3-carboxylic acid, 8-(2-amino-6-((1R)-1-(5-chloro(1,1'-biphenyl)-2-yl)-2,2,2-trifluoroethoxy)-4-pyrimidinyl)-, ethyl ester, (3S)-; Rodatristat ethyl (USAN);
|
| 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 |
| 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 (169.48 mM)
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|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (3.53 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 20.8 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 | 1.6948 mL | 8.4740 mL | 16.9480 mL | |
| 5 mM | 0.3390 mL | 1.6948 mL | 3.3896 mL | |
| 10 mM | 0.1695 mL | 0.8474 mL | 1.6948 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.
Link: https://clinicaltrials.gov/ct2/show/NCT05933447
Conditions:HealthyLink: https://clinicaltrials.gov/ct2/show/NCT05684640
Conditions:HealthyLink: https://clinicaltrials.gov/ct2/show/NCT03924154
Conditions:Pulmonary Arterial Hypertension
Title:Single and Multiple Ascending Doses Clinical Pharmacology Study With KAR5585
Status:Completed
updateDate:2016-08-30
Ctid:NCT02746237
Link: https://clinicaltrials.gov/ct2/show/NCT02746237
Conditions:Pulmonary Arterial HypertensionProducts are for research use only; We do not sell to patients
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