西那西呱(Cinaciguat) - 药物靶点：sGC_专利_临床

概要

基本信息

药物类型

小分子化药

别名

Cinaciguat (JAN/INN)

靶点

sGC

作用机制

sGC刺激剂(可溶性鸟苷酸环化酶复合体刺激剂)

治疗领域

心血管疾病

在研适应症-

非在研适应症

急性失代偿性心力衰竭失代偿性慢性心力衰竭

原研机构

Bayer HealthCare AG

在研机构-

非在研机构

Bayer AG

最高研发阶段终止临床2期

首次获批日期-

最高研发阶段(中国)-

特殊审评-

结构

分子式C36H39NO5

InChIKeyWPYWMXNXEZFMAK-UHFFFAOYSA-N

CAS号329773-35-5

关联

2

项与西那西呱相关的临床试验

NCT01064037 / Terminated临床2期

A Placebo Controlled, Randomized, Double-Blind, Fixed-dose, Multicenter, Phase IIb Study to Investigate the Efficacy and Tolerability of BAY 58-2667 (50 µg/h, 100 µg/h, 150 µg/h) Given Intravenously to Subjects With Acute Decompensated Chronic Congestive Heart Failure (ADHF) Within 12 Hours After Hospital Admission (Pulmonary Artery Catheter eg, Swan-Ganz Not Required)

A placebo controlled, double-blind and randomized study to assess different doses of a new drug (BAY58-2667) given intravenously, to evaluate if it is safe and can help to improve the well-being of patients with acute decompensated heart failure.

开始日期2010-04-01

申办/合作机构

Bayer AG

NCT01067859 / Terminated临床2期

A Placebo Controlled, Randomized, Double-Blind, Fixed-dose, Multicenter, Phase IIb Study to Investigate the Efficacy and Tolerability of Low Dose BAY58-2667 (25 µg/h, 10 µg/h) Given Intravenously to Subjects With Acute Decompensated Chronic Congestive Heart Failure (ADHF)

A placebo controlled, double-blind and randomized study to assess different doses of a new drug (BAY58-2667) given intravenously, to evaluate if it is safe and can help to improve the well-being of patients with acute decompensated heart failure.

开始日期2010-03-01

申办/合作机构

Bayer AG

100 项与西那西呱相关的临床结果

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100 项与西那西呱相关的转化医学

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100 项与西那西呱相关的专利（医药）

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152

项与西那西呱相关的文献（医药）

2024-12-31·Platelets

Role of the NO-GC/cGMP signaling pathway in platelet biomechanics

Article

作者: Pinto-Quintero, Daniel ; Frye, Maike ; Boffito, Marta ; Friebe, Andreas ; Feil, Susanne ; Schäffer, Tilman E ; Seifert, Jan ; Seta, Francesca ; Feil, Robert ; Rodríguez, Johanna G ; Khawaja, Akif A ; Balmes, Aylin ; Emerson, Michael

Cyclic guanosine monophosphate (cGMP) is a second messenger produced by the NO-sensitive guanylyl cyclase (NO-GC). The NO-GC/cGMP pathway in platelets has been extensively studied. However, its role in regulating the biomechanical properties of platelets has not yet been addressed and remains unknown. We therefore investigated the stiffness of living platelets after treatment with the NO-GC stimulator riociguat or the NO-GC activator cinaciguat using scanning ion conductance microscopy (SICM). Stimulation of human and murine platelets with cGMP-modulating drugs decreased cellular stiffness and downregulated P-selectin, a marker for platelet activation. We also quantified changes in platelet shape using deep learning-based platelet morphometry, finding that platelets become more circular upon treatment with cGMP-modulating drugs. To test for clinical applicability of NO-GC stimulators in the context of increased thrombogenicity risk, we investigated the effect of riociguat on platelets from human immunodeficiency virus (HIV)-positive patients taking abacavir sulfate (ABC)-containing regimens. Our results corroborate a functional role of the NO-GC/cGMP pathway in platelet biomechanics, indicating that biomechanical properties such as stiffness or shape could be used as novel biomarkers in clinical research.

2024-06-11·JCI insight

Protein kinase G2 activation restores Wnt signaling and bone mass in glucocorticoid-induced osteoporosis in mice.

Article

作者: Sah, Robert L ; Cabriales, Justin A ; Kalyanaraman, Hema ; Zhuang, Shunhui ; Pilz, Renate B ; Pal China, Shyamsundar

Osteoporotic fractures are a major complication of long-term glucocorticoid therapy. Glucocorticoids transiently increase bone resorption, but they predominantly inhibit bone formation and induce osteocyte apoptosis, leading to bone loss. Current treatments of glucocorticoid-induced osteoporosis aim mainly at reducing bone resorption and are therefore inadequate. We previously showed that signaling via the NO/cGMP/protein kinase G pathway plays a key role in skeletal homeostasis. Here, we show that pharmacological PKG activation with the guanylyl cyclase-1 activator cinaciguat or expression of a constitutively-active, mutant PKG2R242Q restored proliferation, differentiation, and survival of primary mouse osteoblasts exposed to dexamethasone. Cinaciguat treatment of wild type mice or osteoblast-specific expression of PKG2R242Q in transgenic mice prevented dexamethasone-induced loss of cortical bone mass and strength. These effects of cinaciguat and PKG2R242Q expression were due to preserved bone formation parameters and osteocyte survival. The basis for PKG2's effects appeared to be through recovery of Wnt/β-catenin signaling, which was suppressed by glucocorticoids but is critical for proliferation, differentiation, and survival of osteoblast-lineage cells. Cinaciguat reduced dexamethasone activation of osteoclasts, but this did not occur in the PKG2R242Q transgenic mice, suggesting a minor role in osteoprotection. We propose that existing PKG-targeting drugs could represent a novel therapeutic approach to prevent glucocorticoid-induced osteoporosis.

2023-09-01·British journal of pharmacology

Oxidized soluble guanylyl cyclase causes erectile dysfunction in alcoholic mice

Article

作者: Giménez-Gómez, Pablo ; Olivencia, Miguel A ; Angulo, Javier ; Colado, Maria Isabel ; Perez-Vizcaino, Francisco ; Barreira, Bianca ; Fernández, Argentina ; O'Shea, Esther ; Gil de Biedma-Elduayen, Leticia

BACKGROUND AND PURPOSEAlcohol abuse has been associated with erectile dysfunction (ED), but the implicated molecular mechanisms are unresolved. This study analyses the role of alterations in soluble guanylyl cyclase (sGC) in ED.EXPERIMENTAL APPROACHED was analysed in adult male C57BL/6J mice subjected to the Chronic Intermittent Ethanol (CIE) paradigm. Erectile function was assessed in anaesthetised mice in vivo by evaluating intracavernosal pressure (ICP) and in vitro in isolated mice corpora cavernosa (CC) mounted in a myograph. Protein expression and reactive oxygen species were analysed by western blot and dihydroethidium staining, respectively.KEY RESULTSIn CIE mice, we observed a significant decrease in the relaxant response of the CC to stimulation of NO release from nitrergic nerves by electrical field stimulation, to NO release from endothelial cells by acetylcholine, to the PDE5 inhibitor sildenafil, and to the sGC stimulator riociguat. Conversely, the response to the sGC activator cinaciguat, whose action is independent of the oxidation state of sGC, was significantly enhanced in these CC. The responses to adenylyl cyclase stimulation with forskolin were unchanged. We found an increase in reactive oxygen species in the CC from CIE mice as well as an increase in CYP2E1 and NOX2 protein expression. In vivo pre-treatment with tempol prevented alcohol-induced erectile dysfunction.CONCLUSIONS AND IMPLICATIONSOur results demonstrate that alcoholic mice show ED in vitro and in vivo due to an alteration in the redox state of sGC and suggest that sGC activators may be effective in ED associated with alcoholism.

1

项与西那西呱相关的新闻（医药）

2023-03-10

·CPHI制药在线

研发 | 可溶性鸟苷酸环化酶激动剂对心血管的保护及对HFpEF的治疗作用机制

关注并星标CPHI制药在线一氧化氮( NO) 通路受损与多种心血管疾病密切相关，如心力衰竭、高血压和肺动脉高压等。NO供体药物或吸入 NO 在临床治疗中具有较大局限性，而近年来，随着NO-可溶性鸟苷酸环化酶( sGC) -环鸟苷酸( cGMP) 信号通路相关机制的研究深入，sGC 激动剂在心血管系统的临床应用得到了广泛开展。可溶性鸟苷酸环化酶（sGC）主要存在于血小板和血管平滑肌细胞中，是 NO-sGC-环鸟苷酸（cGMP）信号转导途径的中心环节。研究显示，NO-sGC-cGMP轴是调控心血管系统的关键信号转导途径，因此 sGC在心力衰竭、高血压和肺动脉高压等疾病的治疗中具有重要作用。sGC 对NO 具有高度亲和性，在内皮细胞中，炎症因子通过刺激内皮型一氧化氮合酶合成 NO，随之 NO 往深层次浸润，触及平滑肌细胞，从而激活 sGC，被激活的sGC 通过 C 端催化域促进第二信使 cGMP 过度分泌，继而引起一系列心血管反应，包括血管舒张、白细胞聚集和血小板活性增加等。而cGMP 分泌不足或活性减低则会引起内皮功能障碍、血管收缩、血管僵硬和不良重构，以及肾和冠状动脉血流减少。所以sGC 激动剂通过活化下游的cGMP 在抗心肌缺血，改善左心室重塑，改善心力衰竭，抑制炎症和纤维化，改善代谢等方面具有重要作用。 sGC 激动剂对心血管的保护机制可溶性鸟苷酸环化酶激动剂通过活化下游的环鸟苷酸在抗心肌缺血和抗心力衰竭，改善左心室重塑，降低肺动脉压力，抑制炎症和纤维化，改善心肌代谢等方面发挥重大作用。①改善缺血再灌注损伤。sGC激活剂 cinaciguat预处理可减少心肌细胞的坏死和凋亡，减少心肌梗死面积，还可改善低温体外循环心脏停跳术后的心肌和内皮功能，对心肌缺血再灌注损伤起到重要保护作用。此外，研究发现经sGC激活剂 cinaciguat预处理的供体心脏，在进行心脏移植后心脏的左心室功能得到明显改善。研究显示刺激 NO-GC-cGMP 通路的药物依赖于心肌细胞的大电导钙离子激活钾( BK) 通道，可发挥缺血再灌注的相关心脏保护作用，心肌细胞缺少 BK 通道使心脏更易发生缺血再灌注损伤，增加BK活性有利于缺血再灌注心肌的存活。②抗心力衰竭和改善心脏重构。大量的基础研究也相继证实 sGC 激动剂具有抑制心肌纤维化，改善心肌肥厚和心室重塑等心脏保护作用。sGC激活剂 cinaciguat可通过增加蛋白激酶 G(PKG) 的活性，选择性抑制心肌纤维化、氧化应激和心肌细胞的凋亡，进而改善左心室重塑。另外，cinaciguat 可通过阻止糖尿病大鼠模型心脏结构和分子的改变，进而改善心脏功能。③改善心肌代谢效率。研究显示，给予sGC激活剂riociguat 处理后，实验动物的冠状动脉阻力和全身血管阻力均有显著下降，riociguat可明显提高健康幼猪的心脏代谢效率。④降低肺动脉压力和抑制肺血管重塑。研究证实 sGC 激动剂可降低肺动脉压力和阻力，抑制肺血管重塑，提高肺动脉高压患者的运动耐量。2013 年riociguat 被 FDA 批准用于动脉性肺动脉高压和慢性血栓栓塞性肺动脉高压且世界卫生组织心功能分级为Ⅱ～Ⅲ级的患者，取得良好的临床治疗效果。⑤减轻炎症。sGC激活剂 cinaciguat 除了减少炎症和氧化应激，改善心肌细胞功能，还可调节 sGC-cGMP-PKG 信号通路，使肥厚相关激酶钙离子/钙调素依赖性蛋白激酶Ⅱ、蛋白激酶 C和细胞外信号调节激酶2活性正常化，这表明cinaciguat不仅改善心力衰竭，也是心肌肥厚患者的潜在治疗选择。 sGC 激动剂在射血分数保留性心力衰竭（HFpEF）中的作用机制 NO-sGC-cGMP 信号在心血管系统中起着核心作用，特别是在肺动脉高压、高血压和心衰方面。HFpEF是左室舒张期主动松弛功能受损和心肌顺应性降低，即室壁僵硬度增加导致左室舒张期充盈受损、每搏输出量减少和舒张末压增高而发生的心衰。sGC 激动剂在 HFpEF 中的作用机制尚未完全阐明，目前已知的病理生理机制主要包括以下方面：①舒张功能改变。sGC 可降低肌丝钙敏感性，并对跨桥分离产生有益影响，这与NO增加cGMP 生成和加速左室舒张的作用一致，而cGMP 依赖性蛋白激酶的激活，有利于改善心室肥大、舒张和僵硬。②收缩功能改变。在心肌中，sGC 能调节收缩力并减弱肾上腺素能刺激，除了心肌效应外，心脏内皮功能障碍的逆转也能改善舒张功能。③心脏结构变化。靶向 cGMP 信号通路的药物 sGC 激动剂有抗高血压作用，在不影响血压的剂量下可有利地改善心脏重构并减轻心肌纤维化。④依赖 cGMP 的蛋白激酶磷酸化。肌动蛋白是一种锚定在肌节Z线的蛋白质，是心肌被动张力和僵硬度的主要决定因素，可通过磷酸化来调节，这种翻译后修饰促进了肌联蛋白的被动张力的降低，因此有希望成为降低心肌僵硬的治疗靶点。⑤血管功能和硬度改变。HFpEF 患者在运动时全身血管舒张功能明显受损，限制了应激状态下心输出量，表现出血流介导的血管舒张受限。NO 依赖性调节是血管张力的重要调节因素，心衰患者 NO生物利用度的降低导致血管收缩和血管僵硬，进而增加后负荷，同时，NO 生物利用度降低也可能上调交感神经驱动和促进儿茶酚胺释放，并增强内皮素-1诱导的血管收缩。⑥肺动脉高压。在左室射血分数正常的老年患者中，HFpEF 是肺动脉压力升高的最常见原因，肺动脉压升高也预示着 HFpEF 死亡率增加。舒张功能障碍和肺动脉高压之间的显著重叠，研究证实，对肺动脉高压有效的 sGC 激动剂对 HFpEF 也有益。 sGC 激动剂在治疗心力衰竭和肺动脉高压等心血管疾病中具有良好的效果，也是未来心脏缺血再灌注损伤、心肌肥厚和心肌代谢异常等疾病临床治疗的潜在选择。随着对 NO-sGC-cGMP 轴的深入认识和 sGC 的作用机制研究，sGC 激动剂将为心血管疾病的治疗提供了更多的药物选择。在现有的基础上，sGC 激动剂的临床安全性和有效性得到了一定程度的肯定。事实证明，由 sGC激动剂触发 cGMP 的产生可能对心血管疾病的治疗具有更为广阔的市场前景。参考来源： [1]王喜梅,吴永健.可溶性鸟苷酸环化酶激动剂的心血管保护作用研究进展[J].心血管病学进展,2021,42(05):404-407. [2]陆军,金杰妮,王慧,胡静静,俞晴,蔡兆斌.可溶性鸟苷酸环化酶激动剂治疗慢性心力衰竭临床应用进展[J].浙江医学,2021,43(22):2492-2496. [3]贾晓艳,安晋阳,彭可玲,刘永铭.可溶性鸟苷酸环化酶激动剂治疗射血分数保留性心力衰竭的研究进展[J].心血管病学进展,2022,43(02):141-145. 作者简介：小米虫，药品质量研究工作者，长期致力于药品质量研究及药品分析方法验证工作，现就职于国内某大型药物研发公司，从事药品检验分析及分析方法验证。智药研习社近期线下研习会报名来源：CPHI制药在线声明：本文仅代表作者观点，并不代表制药在线立场。本网站内容仅出于传递更多信息之目的。如需转载，请务必注明文章来源和作者。投稿邮箱：Kelly.Xiao@imsinoexpo.com▼更多制药资讯，请关注CPHI制药在线▼点击阅读原文，进入智药研习社~

寡核苷酸

100 项与西那西呱相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
D07577	西那西呱	-	DB16126

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
失代偿性慢性心力衰竭	临床2期	捷克	Bayer AG	2007-12-01
失代偿性慢性心力衰竭	临床2期	塞尔维亚	Bayer AG	2007-12-01
失代偿性慢性心力衰竭	临床2期	立陶宛	Bayer AG	2007-12-01
失代偿性慢性心力衰竭	临床2期	克罗地亚	Bayer AG	2007-12-01
失代偿性慢性心力衰竭	临床2期	俄罗斯	Bayer AG	2007-12-01
失代偿性慢性心力衰竭	临床2期	波兰	Bayer AG	2007-12-01
失代偿性慢性心力衰竭	临床2期	瑞典	Bayer AG	2007-12-01
失代偿性慢性心力衰竭	临床2期	西班牙	Bayer AG	2007-12-01
失代偿性慢性心力衰竭	临床2期	意大利	Bayer AG	2007-12-01
失代偿性慢性心力衰竭	临床2期	爱沙尼亚	Bayer AG	2007-12-01

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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


NCT00559650 (Pubmed \| Eur Heart J)	临床2期	急性失代偿性心力衰竭	139	Cinaciguat	(窪繭願壓積簾餘醖鑰選) = the trial was stopped prematurely due to an increased occurrence of hypotension at cinaciguat doses ≥200 µg/h 觸積鏇製鑰網鏇築齋餘 (鹽鬱鬱廠蓋製壓積壓範 )	-	2013-01-01
				Placebo
ERA2012	N/A	糖尿病肾病	-	Cinaciguat	範襯艱鬱鑰憲糧選淵選(醖淵獵築構觸鹹壓鬱網) = 衊衊壓鏇選餘構蓋範淵構築選積選齋醖壓鑰餘 (製淵網鹹獵鏇艱鬱蓋襯 )	-	2012-05-01
				Diabetic + Cinaciguat treatment	範襯艱鬱鑰憲糧選淵選(醖淵獵築構觸鹹壓鬱網) = 觸齋觸憲獵衊壓鹹艱遞構築選積選齋醖壓鑰餘 (製淵網鹹獵鏇艱鬱蓋襯 )
ERA2012	N/A	糖尿病肾病	-	Cinaciguat	鹹鏇憲製蓋積鹹鹽糧夢(鬱淵鑰製製繭鹹夢鏇顧) = 襯觸鑰鑰鹽艱齋襯夢鹽鬱選鏇範獵糧夢膚遞醖 (獵築淵觸淵構遞顧鏇蓋 )	-	2012-05-01
				Diabetic + Cinaciguat treatment	鹹鏇憲製蓋積鹹鹽糧夢(鬱淵鑰製製繭鹹夢鏇顧) = 網夢膚憲蓋獵膚憲蓋窪鬱選鏇範獵糧夢膚遞醖 (獵築淵觸淵構遞顧鏇蓋 )
ERA2012	N/A	糖尿病肾病	-	Cinaciguat	網鬱衊積築廠艱積築艱(範構蓋鹽窪夢鑰夢積醖) = 鑰鹽蓋構艱鏇襯選鏇繭糧夢艱鏇糧繭顧廠壓鏇 (窪顧壓膚構獵窪簾艱觸 )	-	2012-05-01
				Diabetic + Cinaciguat treatment	網鬱衊積築廠艱積築艱(範構蓋鹽窪夢鑰夢積醖) = 夢窪築顧遞廠繭觸蓋鏇糧夢艱鏇糧繭顧廠壓鏇 (窪顧壓膚構獵窪簾艱觸 )
ERA2012	N/A	糖尿病肾病	-	Cinaciguat	糧築壓遞鬱簾獵夢鹽醖(衊願淵窪鑰繭醖窪觸鹹) = 獵蓋夢觸鏇願獵繭餘窪遞顧觸壓顧願膚選構築 (淵醖齋鬱構蓋鹹夢壓鏇 )	-	2012-05-01
				Diabetic + Cinaciguat treatment	糧築壓遞鬱簾獵夢鹽醖(衊願淵窪鑰繭醖窪觸鹹) = 膚簾鹽窪構繭積簾鬱憲遞顧觸壓顧願膚選構築 (淵醖齋鬱構蓋鹹夢壓鏇 )