An Open-label, Multicentre Study to Evaluate the Safety and Efficacy of Zamicastat as Adjunctive Therapy in Long-term Treatment of Pulmonary Arterial Hypertension (PAH) Disease

This study aims to assess the safety and tolerability of the individual highest tolerated zamicastat doses, achieved in the study BIA-51058-201, during long-term treatment in Pulmonary Arterial Hypertension (PAH) disease.

开始日期2019-06-26

申办/合作机构

BIAL-Portela & Cia SA

NCT04316143

/ Completed临床2期

An Open-label, Multicentre Study to Evaluate Pharmacokinetics, Safety and Efficacy of Zamicastat as Adjunctive Therapy in Pulmonary Arterial Hypertension (PAH)

This Study evaluates the pharmacokinetic (PK) profile of different zamicastat doses in Pulmonary arterial hypertension (PAH) patients to find the most promising therapeutic dosage range for the treatment of PAH disease

开始日期2019-06-03

申办/合作机构

BIAL-Portela & Cia SA

NCT04069130

/ Completed临床1期

An Open-Label Study to Assess the Absorption, Distribution, Metabolism and Excretion, Including the Mass Balance Recovery, Metabolite Profiling and Identification, of [14C] Labelled BIA 5-1058 Following a Single Oral Dose Administration in Healthy Male Subjects

The purpose of the study is to determine the mass balance recovery in expired air, urine and faeces after a single oral dose of 400 mg 14C-labeled BIA 5-1058; to provide plasma, urine and faecal samples for metabolite profiling and structural identification; and determine the routes and rates of elimination of [14C]-BIA 5-1058

开始日期2019-01-22

申办/合作机构

BIAL-Portela & Cia SA

100 项与 Zamicastat 相关的临床结果

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100 项与 Zamicastat 相关的转化医学

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100 项与 Zamicastat 相关的专利（医药）

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项与 Zamicastat 相关的文献（医药）

2025-08-01·DRUG METABOLISM AND DISPOSITION

Human metabolism of zamicastat, an oral dopamine β-hydroxylase inhibitor

Article

作者: Bonifácio, Maria João ; Araújo, Franscisca ; Fernandes-Lopes, Carlos ; Magalhães, Luís ; Holenz, Joerg ; Kiss, László E ; Loureiro, Ana Isabel ; Beliaev, Alexander

The absorption, metabolism, and excretion of zamicastat, a dopamine β-hydroxylase inhibitor, were investigated in healthy male subjects following a single oral dose of 400 mg [¹⁴C]-zamicastat. The mean recovery of total administered radioactivity averaged 86% after 336 hours. Feces was the major route of elimination, representing 69% of the administered dose (with 40% of unchanged compound), 14% were excreted in urine and 2.3% in expired air. The total radioactivity peaked in plasma between 4 and 48 hours, with unchanged zamicastat accounting for <1% of the total circulating radioactivity. The long terminal half-life of total radioactivity (153 hours) was primarily attributed to [¹⁴C]-thiocyanic acid, representing the main circulating metabolite (69.1% of the total circulating radioactivity). Few other minor metabolites were identified in circulation, resulting from multistep reactions involving the desulfuration of zamicastat followed by several phase I and phase II metabolic reactions, such as oxidation and methylation on the benzyl moiety and glucuronic acid conjugation. Although cytochrome P450 was responsible for some zamicastat metabolism, the phenotyping in human hepatocytes showed that the 2 main metabolites observed were not present in vivo. Additionally, only trace levels of thiocyanic acid were observed. This study provides insights into the human elimination routes of zamicastat [¹⁴C]-radiolabeled in the imidazole-thione ring, uncovering an unexpected major, multistep metabolite of zamicastat into thiocyanic acid, highlighting a major in vitro-in vivo difference in zamicastat metabolism. SIGNIFICANCE STATEMENT: The absorption, distribution, metabolism, and excretion of a single radioactive oral dose of zamicastat was evaluated. After oral administration, [¹⁴C]-zamicastat was extensively metabolized with the release of [¹⁴C]-thiocyanic acid that was responsible for the long-lasting circulating radioactivity. Few minor metabolites were identified in circulation. Across species in vitro studies have shown a completely different profile from human metabolism with only trace levels of [¹⁴C]-thiocyanic acid observed, precluding the prediction of the extensive zamicastat metabolism observed in humans.

2024-11-25·XENOBIOTICA

Metabolism and disposition of zamicastat in rats

Article

作者: Soares-da-Silva, Patrício ; Dória, Maria Luisa ; Bonifácio, Maria João ; Holenz, Joerg ; Kiss, László E. ; Beliaev, Alexandre ; Araújo, Francisca ; Loureiro, Ana Isabel

The metabolism and disposition of zamicastat, a reversible dopamine β-hydroxylase (DβH) inhibitor, developed for treatment of Pulmonary Arterial Hypertension (PAH), were investigated in rats after oral and intravenous administration of [¹⁴C]-zamicastat.Zamicastat was rapidly absorbed and widely distributed to peripheral tissues, with total radioactivity almost completely recovered 168 h post-dose. Its main route of excretion was via faeces, whilst urine and expired air had minor roles.Maximum plasma concentration of zamicastat-related radioactivity occurred in the first hours, remaining quantifiable up to 144 h. The unchanged zamicastat plasma peak was 2 h post-dose and declined to low levels over 24 h.Zamicastat metabolism occurs largely during the first 8 h with only one metabolite identified in the latest time-point (96 h), the isothiocyanic acid/thiocyanic acid (tautomeric forms). Zamicastat metabolic pathway involved multiple reactions comprising desulphurisation, oxidative desulphurisation, N-debenzylation followed by further oxidation or N-acetylation, and the unexpected multistep metabolic pathway leading to isothiocyanic acid/thiocyanic acid.

2024-11-01·JOURNAL OF CLINICAL PHARMACOLOGY

Drug‐Drug Interaction between Oral Zamicastat and Continuous Epoprostenol Infusion at Steady‐State Conditions in Healthy Subjects

Article

作者: Henriques, Sara Carolina ; Magalhães, Luís ; Gama, Helena ; Soares‐da‐Silva, Patrício ; Silva, Nuno ; Almeida, Luis ; Fonseca, Marlene ; Guimarães, Andreia

Abstract:

This study intended to evaluate the interactions between zamicastat and epoprostenol in healthy human subjects. This was a single‐center, open‐label, two‐period study. In period 1, epoprostenol 8 ng/kg/min was administered alone. In period 2, epoprostenol 8 ng/kg/min was administered following an 8‐day treatment with zamicastat. Since the initial dose of epoprostenol showed to be insufficiently tolerated, it was decreased to 6 ng/kg/min. Blood samples were collected to determine the metabolites of epoprostenol and concentrations of zamicastat and its metabolites. A total of 54 subjects were enrolled and data from 28 subjects were available for pharmacokinetic analysis. The epoprostenol plus zamicastat‐to‐epoprostenol geometric means ratio (GMR) and corresponding 90% confidence interval (CI) for Cav,ss and area under the plasma concentration–time curve from time 0 up to 16 h at steady state (AUC0‐16,ss) of the metabolites of epoprostenol were within the acceptance bioequivalence range (80.00%‐125.00%). The intrasubject coefficient of variation (ISCV) was below 10% for both parameters, on both metabolites. For zamicastat AUC0‐τ,ss, the zamicastat plus epoprostenol‐to‐zamicastat GMR and corresponding 90% CI were within the bioequivalence acceptance range, while for zamicastat Cmax,ss, the lower limit of the 90% CI was slightly below the acceptance range. For zamicastat metabolites, Cmax,ss and AUC0‐τ,ss and the zamicastat plus epoprostenol‐to‐zamicastat GMR were below the acceptance bioequivalence range. ISCV was between 30% and 41% for Cmax,ss and between 21% and 41% for AUC0‐τ,ss, for zamicastat and both metabolites. This study showed that the administration of zamicastat did not significantly modify the cardiovascular effects of epoprostenol and that the interactions between zamicastat and epoprostenol are not expected to be clinically relevant.

项与 Zamicastat 相关的新闻（医药）

2025-11-25

·智药邦

arXiv｜符号神经生成在先导化合物发现中的应用

2025年10月27日，BITS Pilani大学、剑桥大学、新南威尔士大学以及德里大学等研究团队在arXiv上发表文章，题为“Symbolic Neural Generation with Applications to Lead Discovery in Drug Design”。作者研究了一类混合神经符号模型，该模型将符号学习与神经推理结合，用以构建满足形式化正确标准的数据生成器。在符号神经生成器(SNG)中，符号学习器根据少量实例推导可行数据的逻辑规范。每条规范反过来约束神经生成器所接收的条件信息，使其拒绝任何违反符号规范的生成实例。文章实现了一个将受限形式的归纳逻辑程序设计(ILP)与大语言模型(LLM)相结合的SNG，并在药物早期设计中进行了评估。主要关注点是SNG所产生的描述以及其生成的潜在抑制剂分子集合。在基准问题中，SNG的表现与当前最先进方法在统计上相当；在靶点理解不足的探索性问题中，所生成分子展现出的结合亲和力可与领先的临床候选物相媲美。专家进一步认为，符号规范可作为有用的初步筛选条件，其中若干生成分子被识别为具有合成与湿实验室测试价值的候选物。代码仓库： https://github.com/tirtharajdash/LMLFStar 背景随着现代预训练的大型神经模型已经能够逼近极其广泛的概率分布，新的挑战在于如何以可验证的方式对其进行约束，使其专注于特定任务。从原则上说，这一目标既可以通过纯符号方法实现，也可以通过纯连接主义方法实现。对于一个符号生成器，需要找到某种符号描述S，其中包含对所有相关可能实例的集合U中元素的概率值。随后，这种符号描述可以直接用于采样生成实例。然而困难在于，符号表示通常不够细致，无法表达极其复杂的概率分布；此类分布更适合通过神经网络使用的高维实向量编码来逼近。这在利用语言模型获取复杂条件概率分布时尤为明显。对于纯连接主义方法，神经网络可以对诸如Φ(·)之类的谓词进行编码。问题在于，如果数据样本极少，这种编码会效果不佳(LLM已在少样本文本任务中表现出惊人的能力，但目前尚不清楚这种能力能否稳健地扩展到逻辑公式)。此外，神经模型缺乏精确且可验证的形式化描述，这也构成挑战。当然，如果任务还要求描述能够被人类理解，那么神经网络的编码方式将面临众所周知的困难。因此，出于实践考虑，人们对混合系统的兴趣持续存在。混合系统可以由已有模块构建，更易维护，并且更适合可控的实验研究，特别是在每个组件主要负责特定功能的情况下。在本文中，作者提出使用一个符号组件，通过构造谓词Σ(·)的定义来探索Φ(·)的可能近似。每个此类定义都伴随一组实例，这些实例来自某个神经生成模型，并满足Σ(·)。这种使用符号学习器与神经生成器组合的方法构成了符号神经生成器(SNG)。图1展示了理想的期望结果，以及实际结果。按照定义，SNG属于类别图2(B)中系统的一个子类。图1 (a)理想情况下，希望生成满足Φ(x)为真的实例集合中的实例；(b)当Φ(·)未知时，使用符号学习器得到的假设构造Σ(·)，以近似Φ(·)。希望能从S中高效采样。N是神经生成器获得的实例集合。对于理想的SNG，应满足N ⊆ S ⊆ X；(c)在实践中，符号学习器可能不完美，而神经生成器对条件分布的建模也仅为近似。集合X是生成的、属于S的实例集合。图2 混合神经符号系统的分类方法及示例神经符号生成考虑如下问题：识别集合X={x:x∈U，Φ(x)为真}中的实例，其中条件是Φ(x)未知。然而，确实拥有一些来自U的实例，并且知道它们是否属于X。此外，也可能存在一些与问题相关的背景知识可供利用。在符号神经生成中，利用已有知识研究一个对Φ(·)的近似Σ(·)，并使用该近似来约束后续由神经采样器生成的实例的选择。 SNG实现从图3(b)可见，SNG的实现可以被设计成对集合F中的成对元素(或其加权版本T)进行搜索。在设计实现时，需要回答三个问题：如何识别假设H；如何获得支持集X；如何在空间T中进行搜索。伪代码1是一个为解决获得支持集问题而设计的通用实现，它使用LLM作为从U中生成实例的生成器。SNG的输出是一个三元组(H, X, W)，其中H是由数据构建的可行实例的符号描述，X是满足该描述的生成新实例集合，W是相关权重。图3 SNG偏序语义伪代码1 Gen:神经生成器的基于LLM实现简单SNG的示例一个简单的SNG可以通过以下策略得到，(a)首先在基底偏序上搜索，以找到良好的符号假设H；(b)使用步骤(a)获得的H，并调用过程Gen在给定背景B的基础上获取实例样本。通过一个国际象棋棋局示例来说明链式处理SNG：由白王(WK)、白车(WR)和黑王(BK)组成。关于该棋局存在两个典型任务：学习用于判定非法局面的规则；在黑方行棋(BTM)情形下，预测白方最短几步可以将死黑方(图4(a))。在黑方走棋时，该局面已经是将死，因此是白方必胜(WFW)局面。这类局面仅占整个数据集约0.1%，属于罕见事件。因此SNG的目标是识别一个描述WFW的符号假设以及为该罕见事件生成样本实例。图4 国际象棋棋局示例 Gen 迭代结果示例下图展示了使用GPT-4o作为语言模型、最大样本数量设为30时，过程Gen迭代结果。由图5可知，使用符号模型时，LLM的条件生成能力会逐步提升；鉴于WFW这一概念的正例数量极少，在没有符号理论且Zero-shot的情况下，LLM未能生成任何正例。图5 每次Gen迭代中生成的WFW实例数量在先导化合物发现中应用SNG 案例1：具有大量配体的已充分研究的靶点在两个研究充分的激酶抑制剂上进行受控评测，分别为JAK2(4100个带标签的分子,其中3700个为活性)以及DRD2(4070个带标签的分子，其中3670个为活性)。在本案例研究中，仅使用1个因素，即估计结合亲和力。实验方法步骤如下，首先确定因子集合F及其他约束。随后获取数据实例，包括正例、反例以及未标注样本。最后使用背景知识B、数据D、因子F以及其他约束，使用GenMol生成一组分子并评估所生成分子的质量。图6 激酶抑制剂JAK2及DRD2的实验结果结果如图6所示，SNG的表现至少与LMLF++持平，甚至更好。此外，一个理想的先导化合物生成器应能提出新颖的分子。对JAK问题而言，这并不容易，因为已知抑制剂数量非常多。图7表明GenMol生成的分子仍具有相当的结构新颖性。这部分归因于LLM的prompt，意在生成不属于任何已知化学数据库的分子。图7 使用GPT-4o生成分子的潜在新颖性案例2：对靶点理解不足且抑制剂稀少的情形本研究使用人类多巴胺β-羟化酶(DBH)二聚体的计算模型生成小分子，使其在模拟环境下具有比最新一代DBH抑制剂至少同等或更好的IC50与KD值。使用5种已知的DBH抑制剂(Tropolone、Disulfiram、Nepicastat、Zamicastat、Etamicastat)作为数据，后三者见图 8。该探索性问题旨在基于5个分子在DBH代理靶点上的结构与抑制效果数据，生成潜在的DBH抑制剂先导分子。已知分子的数量非常少(只有5个)。进行了两类探索实验，分别为In-the-Box探索/Few-shot模式和Out-of-the-Box探索/Zero-shot模式。图8 三种处于不同FDA审批阶段的已知DBH抑制剂图9 Few-shot(1-5)与Zero-shot(6-10)生成的Top-5分子图9展示了GenMol提出的潜在DBH抑制剂，以及它们对4zel蛋白的对接分数。分子1–5是In-the-Box探索/Few-shot模式中按估计亲和力排序的前5名；分子6–10是Out-of-the-Box探索/Zero-shot模式的前5名。在Few-shot模式中，GenMol所用的LLM在生成时具有少量示例；在Zero-shot模式中不提供示例，LLM根据其分子分布生成分子。结果表明，Few-shot模式倾向于生成与现有抑制剂相似(但不同)的分子。Zero-shot模式能够生成与已知抑制剂非常不同的新型分子。从生物学角度，有充分理由相信，分子1–5能够与靶点结合；分子6、7、8和10也有良好的结合可能性；其中生物学家认为6和10特别有趣。从合成角度看，所有分子都可合成，但6–10更可能通过短路线合成(因此可能更便宜)。图10 使用/不使用符号学习所生成分子的预测结合亲和力图10展示了仅使用基于LLM的生成器、且不使用符号理论来约束其输出时的结果。结果显示，符号假设确实在其中发挥了有用作用。总结本文提出了一种神经-符号方法，称为符号神经生成(SNG)。SNG系统的特点在于使用一个(学到的)符号描述约束神经生成器生成数据的过程。符号模型在SNG中起到规范的作用，而神经生成器则起到实现的作用。在基准问题上展示的结果表明，SNG方法可与最先进方法相媲美。然而，更具意义的是探索性研究，它对早期药物设计领域尤为重要，具体体现在，使用极少量的数据实例(本例中仅5个)，生成器的一些结果(尤其是在Zero-shot模式下)可能具有生物学新颖性并可被合成。通过LLM，生成的结果可被专家理解；通过符号模型，对LLM输出的控制与验证也得以实现。本工作可通过多种方式改进与扩展，包括GenMol算法解的质量以及方法效率的优化、更多Out-of-the-Box实验以及符号方面的进一步探索。更广泛地说，SNG系统不仅适用于分子生成，还可用于任何需要生成数据并进行形式验证或人工验证，但尚无正式描述的问题。参考链接： https://doi.org/10.48550/arXiv.2510.23379 --------- End --------- 感兴趣的读者，可以添加小邦微信加入读者实名讨论微信群。添加时请主动注明姓名-企业-职位/岗位或姓名-学校-职务/研究方向。

2021-08-25

·GlobeNewswire

Pulmonary Arterial Hypertension Pipeline Insight Research

Los Angeles, USA, Aug. 24, 2021 (GLOBE NEWSWIRE) -- Pulmonary Arterial Hypertension Pipeline Insight Research Report Around 55+ key companies are developing therapies for Pulmonary Arterial Hypertension, among which the drug of Liquidia Technologies is in the advanced stage (Pre Registration) DelveInsight’s “Pulmonary Arterial Hypertension (PAH) Pipeline Insight” report provides comprehensive insights about 55+ companies and 55+ pipeline drugs in the Pulmonary Arterial Hypertension pipeline landscapes. It comprises Pulmonary Arterial Hypertension pipeline drug profiles, including clinical and non-clinical stage products. It also includes the Pulmonary Arterial Hypertension therapeutics assessment by product type, stage, route of administration, and molecule type and further highlights the inactive Pulmonary Arterial Hypertension pipeline products. Some of the key takeaways from the Pulmonary Arterial Hypertension Pipeline Report Get an overview of pipeline landscape @ Pulmonary Arterial Hypertension Clinical Trials Analysis Pulmonary Arterial Hypertension (PAH) is a rare, progressive disorder characterized by high blood pressure in the arteries of the lungs for no apparent reason. Pulmonary Arterial Hypertension Emerging Drugs Sotatercept is a first-in-class therapeutic fusion protein composed of the extracellular domain of human activin receptor type IIA, fused to the Fc domain of human immunoglobulin G1 (IgG1). The United States Food and Drug Administration (FDA) has granted Orphan Drug designation and Breakthrough Therapy designation to sotatercept for the treatment of PAH; the European Medicines Agency (EMA) has granted Priority Medicines (PRIME) designation to sotatercept for the treatment of PAH. Sotatercept is in Phase III clinical trials for the treatment of PAH. LIQ861 is an investigational, inhaled dry powder formulation of treprostinil designed using the Company’s novel PRINT technology and engineered to enhance deep-lung delivery of treprostinil in PAH patients using a convenient, palm-sized dry powder inhaler. Liquidia resubmits New Drug Application for LIQ861 under the 505(b)(2) regulatory pathway for the treatment of pulmonary arterial hypertension (PAH). Gossamer Bio is developing Seralutinib (GB002) for the treatment of Pulmonary Arterial Hypertension. It is currently in the Phase II stage of development (NCT04456998). It acts as an inhibitor of Platelet-derived growth factor receptors, CSF1R, c-KIT. Bial is developing Zamicastat for the treatment of Pulmonary Arterial Hypertension. It is currently in the Phase II stage of development (NCT04316143). It acts as an inhibitor of Dopamine beta-hydroxylase. For further information, refer to the detailed report @ Pulmonary Arterial Hypertension Pipeline Therapeutics Scope of Pulmonary Arterial Hypertension Pipeline Drug Insight · Pulmonary Arterial Hypertension Therapies Late-stage (Phase III) · Pulmonary Arterial Hypertension Therapies Mid-stage (Phase II)· Pulmonary Arterial Hypertension Therapies Early-stage (Phase I) · Pulmonary Arterial Hypertension Preclinical stage and Discovery candidates · Discontinued and Inactive candidates · Epoprostenol receptor agonists· Activin inhibitors· Platelet-derived growth factor receptor antagonists· Dopamine beta-hydroxylase inhibitors· Vasoactive intestinal peptide type II receptor agonists· Angiogenesis inhibitors; Bcr-abl tyrosine kinase inhibitors · Cyclin-dependent kinase 4 inhibitors; Cyclin-dependent kinase 6 inhibitors· Galectin 3 inhibitors · Peptides· Monoclonal antibodies· Small molecules · Proteins· Gene therapy · Parenteral · Oral· Intravenous· Subcutaneous · Monotherapy· Combination· Mono/Combination Key Questions regarding Current Pulmonary Arterial Hypertension Treatment Landscape and Emerging Therapies Answered in the Pipeline Report Table of Contents Get a customized pipeline report @ Pulmonary Arterial Hypertension Drugs Pipeline Report Other Reports About DelveInsightDelveInsight is a leading Business Consultant, and Market Research firm focused exclusively on life sciences. It supports Pharma companies by providing comprehensive end-to-end solutions to improve their performance. It also provides Healthcare Consulting services comprising credible market analysis that will help accelerate the business growth and overcome challenges with a practical approach.

基因疗法抗体孤儿药突破性疗法First in Class

100 项与 Zamicastat 相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
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研发状态

10 条进展最快的记录,

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适应症	最高研发状态	国家/地区	公司	日期
肺动脉高压	临床2期	奥地利	BIAL-Portela & Cia SA	2019-06-03
肺动脉高压	临床2期	德国	BIAL-Portela & Cia SA	2019-06-03
肺动脉高压	临床2期	意大利	BIAL-Portela & Cia SA	2019-06-03
肺动脉高压	临床2期	葡萄牙	BIAL-Portela & Cia SA	2019-06-03
肺动脉高压	临床2期	西班牙	BIAL-Portela & Cia SA	2019-06-03
肺动脉高压	临床2期	乌克兰	BIAL-Portela & Cia SA	2019-06-03
肺动脉高压	临床2期	英国	BIAL-Portela & Cia SA	2019-06-03
心脏衰竭	临床1期	英国	BIAL-Portela & Cia SA	2018-04-09
慢性心力衰竭	临床1期	荷兰	BIAL-Portela & Cia SA	2011-03-01
高血压	临床1期	荷兰	BIAL-Portela & Cia SA	2011-03-01

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT04316143 (CTgov)	临床2期	肺动脉高压	33	Oral zamicastat (50 mg Zamicastat)	構構窪醖選選襯廠繭製(夢網顧窪餘艱衊製鹹簾) = 顧鏇簾獵鹽簾蓋鹽淵獵淵鬱觸鬱範繭餘簾鏇選更多	-	2024-10-15
				Oral zamicastat (100 mg Zamicastat Once Daily)	構構窪醖選選襯廠繭製(夢網顧窪餘艱衊製鹹簾) = 壓構壓廠鬱鑰淵鬱糧衊淵鬱觸鬱範繭餘簾鏇選 (衊壓衊蓋製鹽遞襯憲膚, 44.6) 更多