Rodatristat
(Synonyms: KAR5417) 目录号 : GC63842
Rodatristat (KAR5417) 是一种有效的 tryptophan hydroxylase 1 (TPH1) 和 TPH2 抑制剂，其 IC50 值分别为 33 nM 和 7 nM，并显著降低小鼠肠道中的血清素 (5-HT) 水平。
Cas No.:1673568-73-4
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Rodatristat (KAR5417) is a potent tryptophan hydroxylase 1 (TPH1) and TPH2 inhibitor with IC50s value of 33 nM and 7 nM, respectively, and shows robust reduction of intestinal serotonin (5-HT) levels in mice[1].
Rodatristat (10-50 mg/kg; oral administration; mice) treatment decreases intestinal 5-HT concentrations at 50 mg/kg, their efficacy drop off significantly at the lower 10 mg/kg dose[1].
[1]. Goldberg DR, et al. Optimization of spirocyclic proline tryptophan hydroxylase-1 inhibitors. Bioorg Med Chem Lett. 2017 Feb 1;27(3):413-419.
| Cas No. | 1673568-73-4 | SDF | Download SDF |
| 别名 | KAR5417 | ||
| 分子式 | C27H27ClF3N5O3 | 分子量 | 561.98 |
| 溶解度 | DMSO : 20 mg/mL (35.59 mM; ultrasonic and warming and heat to 80°C) | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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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 |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
Novel Mechanisms Targeted by Drug Trials in Pulmonary Arterial Hypertension
Chest 2022 Apr;161(4):1060-1072.PMID:34655569DOI:10.1016/j.chest.2021.10.010.
Pulmonary arterial hypertension (PAH) is a rare disease associated with abnormally elevated pulmonary pressures and right heart failure resulting in high morbidity and mortality. Although the prognosis for patients with PAH has improved with the introduction of pulmonary vasodilators, disease progression remains a major problem. Given that available therapies are inadequate for preventing small-vessel loss and obstruction, there is active interest in identifying drugs capable of targeting angiogenesis and mechanisms involved in the regulation of cell growth and fibrosis. Among the mechanisms linked to PAH pathogenesis, preclinical studies have identified promising compounds that are currently being tested in clinical trials. These drugs target seven of the major mechanisms associated with PAH pathogenesis: bone morphogenetic protein signaling, tyrosine kinase receptors, estrogen metabolism, extracellular matrix, angiogenesis, epigenetics, and serotonin metabolism. In this review, we discuss the preclinical studies that led to prioritization of these mechanisms, and discuss completed and ongoing phase 2/3 trials using novel interventions such as sotatercept, anastrozole, Rodatristat ethyl, tyrosine kinase inhibitors, and endothelial progenitor cells, among others. We anticipate that the next generation of compounds will build on the success of the current standard of care and improve clinical outcomes and quality of life for patients with PAH.
A trial design to maximize knowledge of the effects of Rodatristat ethyl in the treatment of pulmonary arterial hypertension (ELEVATE 2)
Pulm Circ 2022 May 11;12(2):e12088.PMID:35795492DOI:10.1002/pul2.12088.
Serotonin plays a key role in the development and maintenance of the pathobiology associated with pulmonary arterial hypertension (PAH). Platelet-driven and locally produced serotonin from lung tissue and arterial endothelial cells induce excessive growth of pulmonary artery smooth muscle cells. The unchecked growth of these cells is a major driver of PAH including the remodeling of pulmonary arteries that dramatically reduces the diameter and flexibility of the arterial lumen. Tryptophan hydroxylase 1 (TPH1) is the rate-limiting enzyme for biosynthesis of serotonin and is upregulated in PAH arterial endothelial cells, supporting TPH1 inhibition to treat PAH. Targeting the serotonin pathway via inhibition of peripheral serotonin and local production in diseased tissues, rather than individual receptor-mediated or receptor-independent mechanisms, may result in the ability to halt or reverse pulmonary vascular remodeling. Rodatristat ethyl, a prodrug for Rodatristat, a potent, peripheral inhibitor of TPH1, has demonstrated efficacy in monocrotaline and SUGEN hypoxia nonclinical models of PAH and robust dose-dependent reductions of 5-hydroxyindoleacetic acid, the major metabolite of serotonin in plasma and urine of healthy human subjects. ELEVATE 2 (NCT04712669) is a Phase 2b, double-blind, multicenter trial where patients with PAH are randomized to placebo, 300 or 600 mg twice daily of Rodatristat ethyl. The trial incorporates endpoints to generate essential clinical efficacy, safety, pharmacokinetic, and pharmacodynamic data needed to evaluate the ability of Rodatristat ethyl to ameliorate PAH by halting or reversing pulmonary vascular remodeling through its unique mechanism of TPH1 inhibition. Herein we describe the experimental design highlighting the trial's unique features.