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Rodatristat ethyl Sale

(Synonyms: KAR5585) 目录号 : GC62458

Rodatristat ethyl (KAR5585) 是一种首创的,具有口服活性的 tryptophan hydroxylase 1 (TPH1) 抑制剂,具有体外纳摩尔浓度,可降低 5-hydroxytryptamine (5-HT) 的水平并显着降低肺动脉高压 (PAH),

Rodatristat ethyl Chemical Structure

Cas No.:1673571-51-1

规格 价格 库存
5 mg
¥8,280.00
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10 mg
¥13,050.00
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产品描述

Rodatristat ethyl (KAR5585) is a first-in-class oral tryptophan hydroxylase 1 (TPH1) Inhibitor with nanomolar in vitro potency. Rodatristat ethyl reduces the level of 5-HT and significantly reduces pulmonary arterial hypertension (PAH)[1][2].

Rodatristat ethyl (100 or 200 mg/kg; oral administration; once daily; for 28 days; male Sprague-Dawley rats) treatment decreases erum, gut and lung 5-HT levels in a dose-dependent manner and significantly reduces pulmonary arterial pressure, and pulmonary vessel wall thickness and occlusion in male rats with monocrotaline (MCT)[1].

[1]. Aiello RJ, et al. Tryptophan hydroxylase 1 Inhibition Impacts Pulmonary Vascular Remodeling in Two Rat Modelsof Pulmonary Hypertension. J Pharmacol Exp Ther. 2017 Feb;360(2):267-279.
[2]. Alice MelÃo, MSc. Early Results on Rodatristat Ethyl Support Launch of Phase 2 Trial in PAH Patients. FEBRUARY 4, 2019.

Chemical Properties

Cas No. 1673571-51-1 SDF
别名 KAR5585
分子式 C29H31ClF3N5O3 分子量 590.04
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1 mg 5 mg 10 mg
1 mM 1.6948 mL 8.474 mL 16.948 mL
5 mM 0.339 mL 1.6948 mL 3.3896 mL
10 mM 0.1695 mL 0.8474 mL 1.6948 mL
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Research Update

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.