Portal hypertension (an increase in blood pressure in the portal vein that carries the blood from the intestine and spleen to the liver) underlies most of the serious complications of liver cirrhosis. This randomised placebo controlled study in people with liver cirrhosis evaluates the acute effects serelaxin (RLX030) infusion on portal hypertension and liver blood flow.

开始日期2017-10-18

申办/合作机构

The University of Edinburgh

[+2]

CTR20150806 / Suspended临床3期

一项评价急性心衰患者在标准治疗基础上加用RLX030治疗的有效性、安全性和耐受性的III期临床研究

研究目的是在随机至RLX030或安慰剂组的亚洲AHF患者中，评价就诊后的16个小时内在标准治疗基础上加用RLX030 30 μg/kg/天静脉内输注48小时的有效性、安全性和耐受性。

开始日期2016-04-02

申办/合作机构

Novartis Pharma Stein AG

[+2]

NCT02625922 / Terminated临床2期

A Multicenter, Randomized, Double-blind, Crossover Placebo-controlled Phase II Study to Assess the Effect of Serelaxin Versus Placebo on High-sensitivity Cardiac Troponin I (Hs-cTnI) Release in Patients With Chronic Heart Failure After Exercise When Used in Addition to Standard of Care

This was a multicenter, randomized, double-blind, crossover, placebo-controlled, Phase II clinical study that evaluated the effect of serelaxin versus placebo (both in addition to SoC) on the release of hs-cTnI, in patients with CHF after an exercise testing session.

开始日期2016-02-05

申办/合作机构

Novartis Pharmaceuticals Corp.

100 项与 Serelaxin 相关的临床结果

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100 项与 Serelaxin 相关的转化医学

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100 项与 Serelaxin 相关的专利（医药）

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357

项与 Serelaxin 相关的文献（医药）

2024-10-01·JACC: Heart Failure

Distinct Comorbidity Clusters in Patients With Acute Heart Failure

Article

作者: Greenberg, Barry H ; Teerlink, John R ; Gomez, Karla Arevalo ; Beldhuis, Iris E ; van der Meer, Peter ; Gimpelewicz, Claudio ; Tromp, Jasper ; Lam, Carolyn S P ; Figarska, Sylwia M ; Voors, Adriaan A ; Felker, G Michael ; Davison, Beth A ; Metra, Marco ; Cotter, Gad

BACKGROUNDMultimorbidity frequently occurs in patients with acute heart failure (AHF). The co-occurrence of comorbidities often follows specific patterns.OBJECTIVESThis study investigated multimorbidity subtypes and their associations with clinical outcomes.METHODSFrom the prospective RELAX-AHF-2 (Relaxin for the Treatment of Acute Heart Failure-2) trial, 6,545 patients (26% with HF with preserved ejection fraction, defined as LVEF ≥50%) were classified into multimorbidity groups using latent class analysis. The association between subgroups and clinical outcomes was examined. Validation of these findings was conducted in the RELAX-AHF trial, which comprised 1,161 patients.RESULTSFive distinct multimorbidity groups emerged: 1) diabetes and chronic kidney disease (CKD) (often male, high prevalence of CKD and diabetes mellitus); 2) ischemic (ischemic HF); 3) elderly/atrial fibrillation (AF) (oldest, high prevalence of AF); 4) metabolic (obese, hypertensive, more often HF with preserved ejection fraction); and 5) young (fewest comorbidities). After adjusting for confounders, patients in the diabetes and CKD (HR: 1.80; 95% CI: 1.50-2.20), elderly/AF (HR: 1.42; 95% CI: 1.20-1.70), and metabolic (HR: 1.40; 95% CI: 1.20-1.80) groups had higher rates of the composite outcome than patients in the young group, primarily driven by differences in rehospitalization. Treatment allocation (placebo or serelaxin) modified these associations (P_interaction <0.001). Serelaxin-treated patients in the young group were associated with a lower risk for all-cause mortality (HR: 0.59; 95% CI: 0.40-0.90). Similarly, patients from the RELAX-AHF trial clustered in 5 multimorbidity groups. The clinical characteristics and associations with outcomes could also be validated.CONCLUSIONSComorbidities naturally clustered into 5 mutually exclusive groups in RELAX-AHF-2, showing variations in clinical outcomes. These data emphasize that the specific combination of comorbidities can influence adverse outcomes and treatment responses in patients with AHF.

2024-09-01·Biochemical Pharmacology

Engineering a long acting, non-biased relaxin agonist using Protein-in-Protein technology

Article

作者: Agoulnik, Alexander I ; Lindsay, Ronald M ; Kocan, Martina ; Peng, Yingjie ; Myhr, Courtney ; DiStefano, Peter S ; Kaftanovskaya, Elena M ; Agoulnik, Irina U ; Bathgate, Ross A D

The peptide hormone relaxin plays a critical role in tissue remodeling in a variety of tissues through activation of its cognate receptor, RXFP1. Relaxin's ability to modify extracellular matrices has provided a strong rationale for treating fibrosis in a variety of tissues. Treatment with recombinant relaxin peptides in clinical studies of heart failure has not yet proven useful, likely due to the short half-life of infused peptide. To circumvent this particular pharmacokinetic pitfall we have used a Protein-in-Protein (PiP) antibody technology described previously, to insert a single-chain human relaxin construct into the complementarity-determining region (CDR) of an immunoglobulin G (IgG) backbone, creating a relaxin molecule with a half-life of ∼4-5 days in mice. Relaxin-PiP biologics displaced Europium-labeled human relaxin in RXFP1-expressing cells and demonstrated full agonist activity on both human and mouse RXFP1 receptors. Relaxin-PiPs did not show signal transduction bias, as they activated cAMP in THP-1 cells, and cGMP and pERK signaling in primary human cardiac fibroblasts. In an induced carbon tetrachloride mouse model of liver fibrosis one relaxin-PiP, R2-PiP, caused reduction of liver lesions, ameliorated collagen accumulation in the liver with the corresponding reduction of Collagen1a1 gene expression, and increased cell proliferation in hepatic parenchyma. These relaxin biologics represent a novel approach to the design of a long-acting RXFP1 agonist to probe the clinical utility of relaxin/RXFP1 signaling to treat a variety of human fibrotic diseases.

2024-09-01·Hypertension

Clinical Management of Primary Aldosteronism: An Update

Review

作者: Seccia, Teresa M. ; Rossitto, Giacomo ; Rossi, Gian Paolo ; Rossi, Federico Bernardo ; Guarnieri, Chiara ; Seccia, Teresa M

Despite carrying an excess risk of cardiovascular events, primary aldosteronism (PA) is a commonly overlooked secondary form of arterial hypertension. An increased awareness of its high prevalence and broader screening strategies are urgently needed to improve its detection rate and allow early diagnosis and targeted treatment. For patients with unilateral PA, these measures can correct hyperaldosteronism and ensure cure of hypertension, even when resistant to drug treatment, thus preventing adverse cardiovascular events. Among these, atrial fibrillation is the most common, but left ventricular hypertrophy, stroke, chronic kidney disease, and myocardial infarction also occur more often than in patients with hypertension and no PA. Young patients, who have higher chances of being cured long term, and high-risk patients, such as those with stage III or resistant hypertension, are those who will benefit most from an early diagnosis of PA. Therefore, the implementation of strategies to detect PA by a simplified diagnostic algorithm is necessary. In the patients who seek for surgical cure, adrenal vein sampling is key for the identification of unilateral PA and the achievement of optimal outcomes. Unfortunately, being technically demanding and poorly available, adrenal vein sampling represents the bottleneck in the workup of PA. Considering the novel knowledge generated in the past 5 years in many studies, particularly in the AVIS-2 study (Adrenal Vein Sampling International Study-2), based on 4 decades of experience at our center and on the last guidelines, we herein provide an update on the management of PA with recommendations for drug treatment and strategies to avoid adrenal vein sampling wherever it is poorly, or not, available.

项与 Serelaxin 相关的新闻（医药）

2024-08-12

·新药前沿

First in Class心衰靶点RXFP1诺华、BMS失利后，礼来、AZ继续前行

First in Class类新药开发绝非易事，内外部的经验皆可借鉴。【First in Class类新药开发系列】将通过一些案例的介绍，希望能够给国内生物医药公司First in Class类新药开发提供经验和思考。靶点RXFP1机制探索松弛素家族肽受体1(RXFP1)是一种多结构域G蛋白偶联受体(GPCR)，其胞外结构域由低密度a类蛋白（LDLa）和富含亮氨酸的重复序列(LRR)组成。富含亮氨酸重复序列结构域可作为三类蛋白质激动剂的配体结合位点：糖蛋白激素、R-spondins和松弛素。 RXFP1是松弛素2(RLN)的受体，松弛素2是生殖和心血管生理的重要调节因子。在女性怀孕期间，RXFP1负责生理变化，包括增加心输出量和重塑生殖组织以促进分娩。RXFP1信号传导还具有调节男性和女性许多器官的生理机能，特别是心脏、肺、肝脏和肾脏。这些器官中的松弛素2激活RXFP1会导致多效性细胞效应，包括血管舒张、血管生成、抗炎反应和通过胶原蛋白降解进行的细胞外基质重塑。因此，RXFP1已成为治疗心血管和纤维化疾病的有希望的治疗靶点。 RXFP1信号转导的机制与其他GPCR的机制明显不同，但仍然知之甚少，进化耦合分析和结构引导功能实验表明，RXFP1通过自抑制机制发出信号（doi:10.1038/s41589-023-01321-6）。短效重组松弛素2 Serelaxin曾在急性心力衰竭试验中表现出短期心力衰竭症状缓解和生物标志物改善。Serelaxin 的半衰期较短，限制了其在慢性心力衰竭维持持续药理作用的用途（doi: 10.1111/bph.16055）。而且动物研究证实（doi:10.1016/j.bcp.2024.116305）：松弛素通过RXFP1介导心血管系统的保护作用。在压力超负荷横主动脉缩窄(TAC)模型中，心脏过度表达RXFP1并补充额外的松弛素可减弱心力衰竭。心肌细胞（CM）特异性RXFP1过表达即使在缺乏内源性松弛素的情况下也能提供针对TAC的保护。这表明RXFP1过表达是治疗心力衰竭的潜在方法，可提供基线保护，并可选择补充松弛素以进行特定激活。新药开发诺华短效重组松弛素-2 Serelaxin在Ⅲ期（RELAX-AHF-2试验对于急性心衰未达到死亡率和心力衰竭恶化主要终点，因此终止慢性心衰研究，2017年）失败之后，百时美施贵宝也连续放弃了2个同类项目：使用Ambrx的 ReCODE平台技术开发的每周一次的聚乙二醇化松弛素ARX720 Relaxin （慢性心力衰竭和心肌病，2022年）和蛋白类药物BMS-986259在Ⅱ期（急性心衰，2023年）。如今，该领域主要由礼来、阿斯利康通过半衰期延长等技术进行新药开发。限于篇幅，主要对礼来LY3540378设计思路进行介绍。礼来的LY3540378（Ⅱ期）礼来开发的LY3540378是一种长效单体融合蛋白，由单链松弛素2类似物以B链/连接子/A链配置与血清白蛋白结合VHH结构域(albVHH)结合，以延长半衰期，是更适合治疗慢性心力衰竭的临床候选药物（doi.org/10.1111/bph.16055）。通过albVHH，LY3540378不仅与人血清白蛋白具有高亲和力结合和运输，而且还与常见临床前物种的血清白蛋白结合，从而允许将临床前观察结果转化为临床开发。对人血清白蛋白的亲和力为81pM，循环血清白蛋白浓度约为35–50g·L−1(525–750μM)，经计算，白蛋白结合的LY3540378大于99.999%。因此，循环中的LY3540378与人血清白蛋白以紧密复合物的形式存在，有效分子量约为87kDa（而未复合的LY3540378分子量21kDa）。这种基于作用机制的分子量增加与白蛋白再循环机制相结合，有效地避免了肾脏过滤。同时，LY3540378具有有利的CMC特性和较低分子量蛋白质治疗剂的成本降低。根据其基于血清白蛋白的半衰期延长机制，LY3540378在大鼠中的半衰期为36.4小时，在猴子中的半衰期为45.7-124小时。 LY3540378的另一个特点是其设计为单体单链松弛素类似物。这种单链模式与LY3540378相对较低的分子量相结合，实现了通过分泌和随后从培养基中纯化最终药物产品而实现的具有成本效益的制造工艺，而无需在纯化后去除C肽和重新折叠双链松弛素。由于内源性人类松弛素-2被认为是在RXFP1处作为单体发出信号，因此由融合蛋白的二价性质驱动的两个RXFP1受体的潜在交联的影响及其临床意义仍有待评估。与其他单体、半衰期延长的松弛素类似物（例如最近报道的脂质化松弛素类似物）相比，LY3540378在大鼠中的半衰期明显更长，为36.4小时。LY3540378的较长半衰期可能提供有吸引力的更平坦的峰谷曲线，类似于妊娠期间观察到的持续暴露，这可以最大限度地发挥长期使用的药理学益处。与内源性人类松弛素-2序列相比，LY3540378仅包含最小的序列变化。松弛素-2B链的第一个氨基酸被去除以提高物理化学稳定性，并利用由甘氨酸和丝氨酸组成的柔性氨基酸接头高效组装为单链融合蛋白。进行了广泛的体外和体内药理学研究，以证明内源性人类松弛素功能特性的保留。LY3540378是一种有效的体外RXFP1激动剂，适用于人类和常见的临床前物种，并且对RXFP2的选择性与天然人类松弛素-2相当。同样，LY3540378在RXFP3和RXFP4受体上没有表现出任何活性。此前已证实，松弛素-2可调节人类妊娠中观察到的血清渗透压变化。LY3540378剂量依赖性地降低了大鼠和小鼠的血清渗透压。然而，给药后第1天，变化幅度从载体治疗中的292.5mOsm·kg−1降至最高剂量LY3540378下的284.5mOsm·kg−1显著限制了该终点支持任何结构-活性关系或药效学持续时间研究的实用性。因此，开发了额外的体内药效学测定来证明LY3540378的作用持续时间。先前有报道称，松弛素、小分子RXFP1激动剂和脂质化B链松弛素类似物在昏迷动物中短暂存在1小时或更短的RXFP1介导的急性心动过速效应。LY3540378在单剂量给药后表现出长时间的心动过速效应，表明LY3540378具有持续的药理作用，适合长期使用。此外，LY3540378还有望通过调节肾脏血液动力学，减轻肾小球负担，改善远端钠输送，从而可能改善慢性心力衰竭患者的容量状态。阿斯利康的AZD3427（Ⅱb期） AZD3427是一种人类重组融合蛋白，由人类IgG1的Fc部分与源自人类松弛素的肽序列连接而成。与内源性人类松弛素类似，AZD3427是RXFP1的选择性激动剂（doi:10.1161/JAHA.123.034067）。在Ia/b期研究中，AZD3427在心力衰竭患者中最后一次给药后的终末半衰期为13至14天，在研究范围内，暴露量与剂量大致成比例增加。观察到的AZD3427药代动力学和药效学特征表明，可以将给药频率降低到每周少于一次。此外，阿斯利康还在开发小分子RFXP1激动剂AZD-5462进入Ⅱb期（设计思路参考doi: 10.1021/acs.jmedchem.3c02183和10.1021/acs.jmedchem.3c02184），与Moderna合作开发的mRNA疗法AZD7970处于临床前阶段，不再赘述。本文由「新药前沿」微信公众号根据公开资料整理编辑，欢迎个人转发至朋友圈。媒体或机构转载授权请在「新药前沿」微信公众号留言公众号名称，审核通过后开通白名单获取转载授权，转载请标识来源。免责声明：本文仅作信息交流之目的，非投资建议或者治疗方案推荐，「新药前沿」微信公众号不对任何主体因使用本文内容而导致的任何损失承担责任。限于作者水平和专业知识所限，如有谬误，欢迎指正！

临床2期临床3期

2024-03-02

·PRNewswire

Global Acute Heart Failure (AHF) Therapeutics Research Report 2022-2024 and 2030: Conventional Therapies Leave Considerable Unmet Needs, Novel Treatments Offer a Ray of Hope

DUBLIN, March 1, 2024 /PRNewswire/ -- The "Acute Heart Failure (AHF) Therapeutics: Global Strategic Business Report" report has been added to ResearchAndMarkets.com's offering. Global Acute Heart Failure (AHF) Therapeutics Market to Reach $2.9 Billion by 2030 The global market for Acute Heart Failure (AHF) Therapeutics estimated at US$599.7 Million in the year 2022, is projected to reach a revised size of US$2.9 Billion by 2030, growing at a CAGR of 21.7% over the analysis period 2022-2030. Cardiac Glycosides, one of the segments analyzed in the report, is projected to record a 22.3% CAGR and reach US$762.4 Million by the end of the analysis period. Taking into account the ongoing post pandemic recovery, growth in the B-Blockers segment is readjusted to a revised 25.1% CAGR for the next 8-year period. The acute heart failure (AHF) market has been significantly impacted by the COVID-19 pandemic and the looming global recession. Despite the challenges, diuretics and vasodilators remain the first-line therapy for AHF, although the efficacy of other known drugs for AHF is limited, hindering their widespread use. Market insights and trajectories indicate a complex landscape influenced by these factors, with varying degrees of competitive market presence among players worldwide in 2022. Recent market activity reflects ongoing efforts to size the AHF market and adapt to the evolving healthcare landscape. Looking ahead, the market outlook suggests continued focus on addressing the challenges posed by COVID-19 and economic uncertainties while exploring opportunities for innovation and growth in AHF therapeutics. The U.S. Market is Estimated at $163.4 Million, While China is Forecast to Grow at 30.4% CAGR The Acute Heart Failure (AHF) Therapeutics market in the U.S. is estimated at US$163.4 Million in the year 2022. China, the world's second largest economy, is forecast to reach a projected market size of US$841.2 Million by the year 2030 trailing a CAGR of 30.4% over the analysis period 2022 to 2030. Among the other noteworthy geographic markets are Japan and Canada, each forecast to grow at 16.3% and 18.4% respectively over the 2022-2030 period. Within Europe, Germany is forecast to grow at approximately 17.1% CAGR. Led by countries such as Australia, India, and South Korea, the market in Asia-Pacific is forecast to reach US$433.4 Million by the year 2030. MARKET OVERVIEW Influencer Market Insights World Market Trajectories Market Outlook Recent Market Activity Sizing the AHF Market Acute Heart Failure - An Overview of the Disease and Available Therapeutics Diuretics and Vasodilators - The First Line Therapy for AHF Other Known Drugs for AHF - Lower Efficacy Thwarts Use Acute Heart Failure (AHF) Therapeutics - Global Key Competitors Percentage Market Share in 2022 (E) Competitive Market Presence - Strong/Active/Niche/Trivial for Players Worldwide in 2022 (E) Impact of Covid-19 and a Looming Global Recession MARKET TRENDS & DRIVERS Conventional Therapies Leave Considerable Unmet Needs Novel Treatments Offer a Ray of Hope Key AHF Therapeutics in the Pipeline Serelaxin Nears Trial Readout form RELAX-AHF-2 Ularitide - A Novel Drug in Development for AHF The Litany of Drug Failures Expands, Emphasis on Prevention Grows Other Promising Drugs under Development Research Findings Kidney Dysfunction - Predictor of Acute Heart failure Genetic Influence on Heart Disease among African Americans Higher Body Mass Index - A Key Risk Factor for AHF Supplemental Oxygen Therapy May not be for All Cases of AHF Macro Growth Drivers Alarming Levels of Cardiovascular Disease (CVD) Prevalence: Key Growth Driver for AHF Therapeutics Ballooning Elderly Population: The Vital Growth Driver for AHF Therapeutics FOCUS ON SELECT PLAYERS (Total 93 Featured) Bayer AG (Germany) Bristol-Myers Squibb Company (USA) Cardiorentis AG (Switzerland) CVie Therapeutics Limited (Taiwan) Cytokinetics, Inc. (USA) Merck & Co. (USA) Novartis AG (Switzerland) Orion Corporation (Finland) PhaseBio Pharmaceuticals, Inc. (USA) For more information about this report visit About ResearchAndMarkets.com ResearchAndMarkets.com is the world's leading source for international market research reports and market data. We provide you with the latest data on international and regional markets, key industries, the top companies, new products and the latest trends. Media Contact: Research and Markets Laura Wood, Senior Manager [email protected] For E.S.T Office Hours Call +1-917-300-0470 For U.S./CAN Toll Free Call +1-800-526-8630 For GMT Office Hours Call +353-1-416-8900 U.S. Fax: 646-607-1907 Fax (outside U.S.): +353-1-481-1716 Logo: SOURCE Research and Markets

AHA会议

2023-06-21

·智慧芽新药科讯

十年磨一剑---阿斯利康的RXFP1激动剂能否拔得头筹？

松弛素是一种多效性激素，在怀孕期间介导全身血流动力学和肾脏适应性变化。松弛素也被证明具有抗纤维化特性，并对心力衰竭有有益作用，例如急性失代偿性心力衰竭(ADHF)。心力衰竭具有较高的发病率和死亡率。其特点是复杂的组织重塑，包括心肌细胞死亡和间质纤维化增加。松弛素激活了许多信号级联反应，这在缺血再灌注和心力衰竭的情况下是有益的。如图1，这些信号通路包括PI3K通路和一氧化氮信号通路。松弛素家族肽受体1 (RXFP1)是松弛素-2的受体，松弛素-2是生殖和心血管生理的重要调节因子。RXFP1是一个经过充分验证的、药理学上重要的GPCR家族1c成员，其被松弛素激素激活与血流动力学、抗纤维化和抗炎特性有关。RXFP1的激活可以降低血管阻力和潜在的肺压，从而增加心输出量，增强肾、肺和肝脏重要中央血管床的灌注。图1 RXFP1介导的信号通路靶向RXFP1的激动剂目前只有一款药物上市，是诺华开发的重组天然激素类似物serelaxin。处于临床阶段的激动剂有松弛素模拟物AZD3427（II期）、小分子AZD5462（I期），凭借新冠疫苗大火的Moderna Therapeutics公司开发的mRNA类激动剂mRNA-0184（I期）。以及临床前靶向RXFP1和RXFP2的多肽激动剂CGEN-25010（无进展）。Serelaxin的心衰3期临床因为试验没有达到一级终点而失败，最后只能选择在俄罗斯上市，且Serelaxin的半衰期只有10分钟，需要静脉注射。松弛素模拟物AZD3427和mRNA-0184也需要注射。为了提高患者的依从性，小分子激动剂的开发具有广阔的市场。小分子靶向RXFP1非常具有挑战，因为缺乏直接的蛋白结构信息，并且早期通过高通量筛选得到的小分子都缺乏成药性。2013年，美国国立卫生研究院对35万多个化合物通过高通量筛选发现了化合物ML290。AZ和BMS均以ML290为先导进行优化，最终AZD5462在2022年6月成为首个进入临床的口服小分子RXFP1激动剂。图2 AZD5462的结构两年一次的 EFMC-ISMC是药物化学和药物发现领域的重要研讨会。在2022年9月的EFMC-ISMC会议上阿斯利康公开了AZD5462的结构信息。如图2，AZD5462结构中含有一个有趣的降冰片烷环，同时连着一个顺式环己烷羧酸片段。AZD5462正处于临床一期试验中，以评估其在日本裔健康志愿者中的安全性、耐受性和药代动力学，使用单次和多次递增剂量给药。对心力衰竭伴射血分数降低(HFrEF)的猕猴进行的临床前研究显示，给药8周后，心脏收缩期功能得到改善，平均动脉血压或心率没有显著升高。AZD5462对RXFP1具有高度选择性，在7个最接近的GPCR中没有活性(大于10µM)，并且与CEREP Safety panel中的靶标没有相互作用。图3 AZD5462的发现-引入苯环的生物电子等排体根据会议披露的SAR信息，简单猜测一下AZD5462的发现过程，这是一个传统药化改构的案例。图3箭头所示为ML290的结构，LogD7.4较高容易带来一些毒性风险。最初将邻氨基苯甲酸片段的苯环替换成非芳香片段，如Rac-4和Rac-5，但都有不同程度的活性下降，清除也变快。如图4所示，改造的关键点是引入了羧酸片段，这可能是想降低LogD7.4或者改善药物的组织分布，从后续给出的Vss看，分布体积也减小了。Rac-12和Rac-13对比，说明了羧酸和氧原子之间隔4个碳原子对活性提升最有利，较Rac-11提升了10倍以上。进一步接上环己烷羧酸片段，并饱和Rac-11中非芳香环的双键得到化合物14，活性较Rac-11提升了10000倍，但化合物14的LogD7.4仍然较高，达到4.9。图4 AZD5462的发现-引入环己烷羧酸进一步，把最右侧的苯环也用非芳香片段替代，以降低脂溶性，减小LogD7.4，引入叔丁基、环丁基、环己基等，得到图5所示的化合物15、AZD5462、16、17、18。活性虽然降低了，但是其他性质得到平衡，比如LogD7.4就在一个合理的范围中，清除率也不会过快。预估的人体给药剂量也在100mg/70kg/d内（除了化合物16的预估剂量达到304/70kg/d）。而化合物17和18中R片段由F改为CN，降低了人体预估剂量却没有被选中，笔者猜测是基于安全性层面的考量。图5 AZD5462的发现-成药性的优化如图6，重新梳理一下AZD5462的各项数据。由于RXFP1激动剂所针对的适应症是慢性病，安全性必然最为重要。AZD5462各项性质均衡，在最为关键的安全性参数的评价中，没有CYP450酶抑制的风险，无TDI风险（CPY3A4/5），无hERG毒性风险，无ames毒性风险。caco-2测试中，虽然efflux达到3.6，有一定的外排，但是吸收较好弥补了外排的风险。虽对OATP1B1 和OATP1B3 转运体有一定程度的抑制，仍需考虑具体给药剂量下血药浓度的影响。并且AZD5462的LogD7.4也因为将两处的芳香环非芳香化，同时引入羧酸片段，成功降低到3.2。CEREP Safety panel中的靶标选择性也大于1000倍。Vss也在合理范围，不会导致组织分布过于广泛而影响药效。大鼠的生物利用度达到58%，虽然食蟹猴的生物利用度只有12%，但是根据AZD5462在不同种属肝细胞中代谢稳定性的差异，预测的人体内的生物利用度达到70%。考虑到以上种种所带来的获益风险比，最终AZD5462进入一期临床评估其对心血管紊乱方面相关疾病的治疗潜力。图6 AZD5462的主要评价数据在智慧芽专利数据库中检索RXFP1，主要是AZ和BMS在布局靶点RXFP1，还未看到国内公司follow的专利公开。阿斯利康申请了一篇专利WO2022122773A1，包含624个实施例，其中就有AZD5462。BMS在2023.5.4公开了4篇RXFP1激动剂专利，第一篇WO2023077041A1，这篇专利只有19个实施例。第二篇WO2023077040A1，包含377个实施例，少部分化合物达到了纳摩尔水平。第三篇WO2023077070A1，包含188个实施例，多数化合物达到了纳摩尔活性水平。从结构上可以看出是在第二篇专利的结构基础上进行进一步优化。第四篇WO2023076626A1，包含976个实施例。结构上延续了第三篇，只是把吡啶替换成了苯环。活性大部分都是纳摩尔水平。自从美国国立卫生研究院首次报道ML290的结构，已过去10年，AZ和BMS进入小分子RXFP1激动剂领域时，都是以ML290为先导，根据传统药化改构的思路优化成药性。2022年在bioRxiv上发表了活性态RFXP1的CryoEM结构，这将促进更多新结构类型的RXFP1小分子激动剂的发现。随着AZD5462进入临床评估安全性和有效性，这一领域的研发热情也再次被点燃，期待更多积极结果的公布，为心血管病人带来福音。参考资料：1.Ram W. Sabnis. Novel RXFP1Modulators for Treating Heart Failure. ACS Med. Chem. Lett. 2022, 13, 1213−1214.2.Maik Gollasch et al; RXFP1 Receptor Activation by Relaxin-2 Induces Vascular Relaxation in Mice via a Gαi2-Protein/PI3Kß/γ/Nitric Oxide-Coupled Pathway. doi: 10.3389/fphys.2018.01234.3.https://drughunter.com/first-disclosures-from-esmc-ifmc-nice-2022/.4.Pamela Brown et al; Recent trends in medicinal chemistry and enabling technologies. Highlights from the Society for Medicines Research Conference. Drugs of the Future 2023, 48(3): 211-219.5.谢伊，人在药途，研发前沿|诺华、AZ、BMS等大厂争先布局的RXFP1，是个什么靶点？6.智慧芽新药情报库.

临床2期临床1期信使RNA临床3期疫苗

100 项与 Serelaxin 相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
D10488	Serelaxin	C01DX21	DB05794

研发状态

批准上市

10 条最早获批的记录,

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适应症	国家/地区	公司	日期
纤维化	俄罗斯	-	2015-01-01
心脏衰竭	俄罗斯	-	2015-01-01
门静脉高血压	俄罗斯	-	2015-01-01

未上市

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
心脏衰竭	临床2期	欧盟	Novartis Europharm Ltd.	2014-01-24
心脏衰竭	临床2期	欧盟	Novartis Europharm Ltd.	2014-01-24
急性失代偿性心力衰竭	临床前	德国	Novartis Pharmaceuticals Corp.	2014-01-31
急性失代偿性心力衰竭	临床前	爱沙尼亚	Novartis Pharmaceuticals Corp.	2014-01-31
急性失代偿性心力衰竭	临床前	斯洛伐克	Novartis Pharmaceuticals Corp.	2014-01-31
急性失代偿性心力衰竭	临床前	拉脱维亚	Novartis Pharmaceuticals Corp.	2014-01-31
急性失代偿性心力衰竭	临床前	俄罗斯	Novartis Pharmaceuticals Corp.	2014-01-31
急性失代偿性心力衰竭	临床前	捷克	Novartis Pharmaceuticals Corp.	2014-01-31
急性失代偿性心力衰竭	临床前	奥地利	Novartis Pharmaceuticals Corp.	2014-01-31
心脏衰竭	临床前	欧盟	Novartis Europharm Ltd.	2014-01-24

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临床结果

适应症

分期

评价

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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


NCT01979614 (Pubmed) 人工标引	临床2期	冠心病	51	serelaxin	糧顧蓋壓選築糧窪糧鹽(夢膚鑰蓋鑰淵範壓夢鹹) = 鏇構夢淵網蓋鬱糧觸衊築糧壓築製鹹衊鏇鏇網 (醖鬱願蓋齋餘鹽淵鬱積 ) 更多	积极	2021-01-01
				Placebo	糧顧蓋壓選築糧窪糧鹽(夢膚鑰蓋鑰淵範壓夢鹹) = 顧醖膚鹽範夢齋蓋夢糧築糧壓築製鹹衊鏇鏇網 (醖鬱願蓋齋餘鹽淵鬱積 ) 更多
NCT02669875 (STOPP, Pubmed \| Trials)	临床2期	纤维化	15	Serelaxin	(願範願鹽窪窪顧簾壓網) = 範壓遞鏇繭膚繭壓醖襯範鬱觸觸繭醖獵製觸積 (製願鬱夢願鹽鹹糧構願, ±3.5)	-	2020-03-12
NCT01870778 (RELAX-AHF-2, Pubmed \| Br Dent J) 人工标引	临床3期	心脏衰竭	6,545	Serelaxin	(鑰製網淵築觸鬱餘鬱壓) = 簾願鏇鬱壓蓋觸蓋積艱淵製壓憲窪廠憲鏇廠願 (製廠願糧願鬱簾淵獵觸 ) 更多	不佳	2019-08-22
				Placebo	(鑰製網淵築觸鬱餘鬱壓) = 遞構築鬱壓網簾遞蓋艱淵製壓憲窪廠憲鏇廠願 (製廠願糧願鬱簾淵獵觸 ) 更多
NCT01979614 (CTgov)	临床2期	冠心病	58	Serelaxin (Serelaxin)	鬱蓋糧構淵顧簾襯蓋醖(簾廠壓膚醖獵製醖夢醖) = 艱壓製糧膚繭鬱齋鑰積鏇廠壓鹽遞築衊鬱製膚 (廠選衊鏇醖積鹹製顧糧, 齋醖壓膚艱願鹽鑰夢鏇 ~ 壓餘膚壓鹹鹹製膚繭衊) 更多	-	2019-07-01
				Placebo (Placebo)	鬱蓋糧構淵顧簾襯蓋醖(簾廠壓膚醖獵製醖夢醖) = 鹹糧鏇獵製鏇艱鏇範築鏇廠壓鹽遞築衊鬱製膚 (廠選衊鏇醖積鹹製顧糧, 廠範醖繭糧鬱夢鏇憲醖 ~ 積蓋網築襯糧窪糧齋淵) 更多
NCT02151383 (RELAX-PEDS-PK, CTgov)	临床2期	急性失代偿性心力衰竭	12	Serelaxin (Serelaxin: Cohort 1)	(鏇鏇醖範鬱願壓憲齋壓) = 鬱艱壓蓋觸鬱繭窪繭觸鏇膚淵糧觸鬱膚鏇鏇齋 (餘繭網繭選築遞膚糧顧, 築鏇憲淵選網淵顧構鏇 ~ 膚蓋顧鹹觸鬱壓蓋衊齋) 更多	-	2019-06-25
				Serelaxin (Serelaxin: Cohort 2)	(鏇鏇醖範鬱願壓憲齋壓) = 範鏇鑰廠醖獵蓋艱顧積鏇膚淵糧觸鬱膚鏇鏇齋 (餘繭網繭選築遞膚糧顧, 獵衊壓淵網網膚鏇襯淵 ~ 憲顧繭蓋簾襯構選齋築) 更多
NCT02064868 (RELAX-AHF-EU, CTgov)	临床3期	急性失代偿性心力衰竭	2,666	Standard of Care+Serelaxin (Serelaxin + Standard of Care)	襯構廠艱構憲壓顧積簾(構糧網醖網構窪製網築) = 夢蓋獵選鹹膚窪鏇襯壓積鹹餘繭鬱醖夢鏇築願 (夢廠遞壓選膚築夢糧衊, 積鬱鹽簾艱憲獵夢願觸 ~ 衊艱範憲襯網選淵獵糧) 更多	-	2019-03-22
				Standard of Care (Standard of Care (SOC))	襯構廠艱構憲壓顧積簾(構糧網醖網構窪製網築) = 顧糧築憲築遞構遞夢鬱積鹹餘繭鬱醖夢鏇築願 (夢廠遞壓選膚築夢糧衊, 鹽繭襯餘範襯鬱廠鏇顧 ~ 繭齋醖顧憲積糧衊襯醖) 更多
NCT02064868 (RELAX-AHF-EU, Pubmed \| Eur J Heart Fail) 人工标引	临床3期	心脏衰竭	2,666	standard of care+serelaxin	鬱觸範願夢艱鬱製鑰淵(獵蓋鏇鹽鏇製築選壓網) = 膚艱願窪鬱夢襯淵襯壓鏇廠鹽鬱淵構簾選範簾 (窪觸獵選觸獵鏇糧廠積 )	积极	2019-03-01
				standard of care	鬱觸範願夢艱鬱製鑰淵(獵蓋鏇鹽鏇製築選壓網) = 艱憲繭膚願淵築膚襯網鏇廠鹽鬱淵構簾選範簾 (窪觸獵選觸獵鏇糧廠積 )
NCT01870778 (RELAX-AHF-2, CTgov)	临床3期	心脏衰竭	6,600	RLX030 (Serelaxin (RLX030))	淵廠獵醖衊願選蓋窪鏇(選獵蓋築製製鑰窪醖願) = 醖醖膚選顧齋遞網襯糧獵醖獵構廠鹹願觸糧網 (淵夢積蓋餘遞簾餘製積, 獵簾範艱鑰積鹹夢鹹醖 ~ 窪鬱夢糧鏇醖襯衊壓鬱) 更多	-	2018-03-30
				Placebo (Placebo)	淵廠獵醖衊願選蓋窪鏇(選獵蓋築製製鑰窪醖願) = 齋網醖鑰構醖膚範齋窪獵醖獵構廠鹹願觸糧網 (淵夢積蓋餘遞簾餘製積, 鑰窪糧衊艱糧構廠艱繭 ~ 窪醖範獵衊製繭夢餘獵) 更多
NCT01979614 (ESC2017)	临床2期	冠心病	62	IV serelaxin (30 Î¼g/kg/24 h)	憲鹹醖蓋選膚繭鏇鬱簾(鏇夢鏇製齋獵廠築鬱夢) = 構衊膚鬱壓顧鏇願鬱夢構窪餘衊鑰獵壓餘廠蓋 (廠鹽齋願製鹽憲廠廠簾 ) 更多	不佳	2017-08-27
				Placebo	憲鹹醖蓋選膚繭鏇鬱簾(鏇夢鏇製齋獵廠築鬱夢) = 壓顧鏇鹹簾夢鑰構製廠構窪餘衊鑰獵壓餘廠蓋 (廠鹽齋願製鹽憲廠廠簾 ) 更多
NCT01982292 (RELAX-REPEAT, CTgov)	临床2期	慢性心力衰竭	321	RLX030 (serelaxin) (RLX030 (Serelaxin))	構膚鹽獵鹽顧範鏇窪觸(鬱襯觸膚膚蓋繭糧積積) = 繭獵廠願糧糧衊艱鑰鏇製醖構築窪鹹艱顧壓憲 (築繭鹹積憲壓淵鹹醖壓, 網廠構膚築壓襯製蓋憲 ~ 齋鹹艱鏇觸壓願醖窪膚) 更多	-	2016-11-09
				Placebo (Placebo)	構膚鹽獵鹽顧範鏇窪觸(鬱襯觸膚膚蓋繭糧積積) = 簾壓鬱襯衊艱夢膚選觸製醖構築窪鹹艱顧壓憲 (築繭鹹積憲壓淵鹹醖壓, 糧齋簾願積鑰繭襯窪鏇 ~ 製艱糧鹽願膚構築積製) 更多