Olinciguat
(Synonyms: IW-1701) 目录号 : GC36801
Olinciguat (IW-1701) 是一种可口服的鸟苷酸环化酶 (guanylate cyclase, sGC) 刺激剂，在纯化的大鼠和人类酶实验和全细胞实验中刺激 sGC，这种作用具有浓度依赖性。
Cas No.:1628732-62-6
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
Olinciguat (IW-1701) is an oral guanylate cyclase (sGC) stimulator with concentration-dependent stimulation of sGC in purified rat and human enzyme assays and a whole cell assay[1].
[1]. Buys ES, et al. Discovery and development of next generation sGC stimulators with diverse multidimensional pharmacology and broad therapeutic potential. Nitric Oxide. 2018 Aug 1;78:72-80.
| Cas No. | 1628732-62-6 | SDF | |
| 别名 | IW-1701 | ||
| Canonical SMILES | FC1=C(C=CC=C1)CN2C(C3=NOC=C3)=CC(C4=NC=C(F)C(NC[C@](C(N)=O)(O)C(F)(F)F)=N4)=N2 | ||
| 分子式 | C21H16F5N7O3 | 分子量 | 509.39 |
| 溶解度 | DMSO: 125 mg/mL (245.39 mM) | 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 | 1.9631 mL | 9.8157 mL | 19.6313 mL |
| 5 mM | 0.3926 mL | 1.9631 mL | 3.9263 mL |
| 10 mM | 0.1963 mL | 0.9816 mL | 1.9631 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。
Olinciguat, a stimulator of soluble guanylyl cyclase, attenuates inflammation, vaso-occlusion and nephropathy in mouse models of sickle cell disease
Br J Pharmacol 2021 Sep;178(17):3463-3475.PMID:33864386DOI:10.1111/bph.15492.
Background and purpose: Reduced bioavailability of NO, a hallmark of sickle cell disease (SCD), contributes to intravascular inflammation, vasoconstriction, vaso-occlusion and organ damage observed in SCD patients. Soluble guanylyl cyclase (sGC) catalyses synthesis of cGMP in response to NO. cGMP-amplifying agents, including NO donors and phosphodiesterase 9 inhibitors, alleviate TNFα-induced inflammation in wild-type C57BL/6 mice and in 'humanised' mouse models of SCD. Experimental approach: Effects of the sGC stimulator Olinciguat on intravascular inflammation and renal injury were studied in acute (C57BL6 and Berkeley mice) and chronic (Townes mice) mouse models of TNFα-induced and systemic inflammation associated with SCD. Key results: Acute treatment with Olinciguat attenuated increases in plasma biomarkers of endothelial cell activation and leukocyte-endothelial cell interactions in TNFα-challenged mice. Co-treatment with hydroxyurea, an FDA-approved SCD therapeutic agent, further augmented the anti-inflammatory effect of Olinciguat. In the Berkeley mouse model of TNFα-induced vaso-occlusive crisis, a single dose of Olinciguat attenuated leukocyte-endothelial cell interactions, improved blood flow and prolonged survival time compared to vehicle-treated mice. In Townes SCD mice, plasma biomarkers of inflammation and endothelial cell activation were lower in olinciguat- than in vehicle-treated mice. In addition, kidney mass, water consumption, 24-h urine excretion, plasma levels of cystatin C and urinary excretion of N-acetyl-β-d-glucosaminidase and neutrophil gelatinase-associated lipocalin were lower in Townes mice treated with Olinciguat than in vehicle-treated mice. Conclusion and implications: Our results suggest that the sGC stimulator Olinciguat attenuates inflammation, vaso-occlusion and kidney injury in mouse models of SCD and systemic inflammation.
Olinciguat, an Oral sGC Stimulator, Exhibits Diverse Pharmacology Across Preclinical Models of Cardiovascular, Metabolic, Renal, and Inflammatory Disease
Front Pharmacol 2020 Apr 8;11:419.PMID:32322204DOI:10.3389/fphar.2020.00419.
Nitric oxide (NO)-soluble guanylate cyclase (sGC)-cyclic 3',5' GMP (cGMP) signaling plays a central role in regulation of diverse processes including smooth muscle relaxation, inflammation, and fibrosis. sGC is activated by the short-lived physiologic mediator NO. sGC stimulators are small-molecule compounds that directly bind to sGC to enhance NO-mediated cGMP signaling. Olinciguat, (R)-3,3,3-trifluoro-2-(((5-fluoro-2-(1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazol-3-yl)pyrimidin-4-yl)amino)methyl)-2-hydroxypropanamide, is a new sGC stimulator currently in Phase 2 clinical development. To understand the potential clinical utility of Olinciguat, we studied its pharmacokinetics, tissue distribution, and pharmacologic effects in preclinical models. Olinciguat relaxed human vascular smooth muscle and was a potent inhibitor of vascular smooth muscle proliferation in vitro. These antiproliferative effects were potentiated by the phosphodiesterase 5 inhibitor tadalafil, which did not inhibit vascular smooth muscle proliferation on its own. Olinciguat was orally bioavailable and predominantly cleared by the liver in rats. In a rat whole body autoradiography study, olinciguat-derived radioactivity in most tissues was comparable to plasma levels, indicating a balanced distribution between vascular and extravascular compartments. Olinciguat was explored in rodent models to study its effects on the vasculature, the heart, the kidneys, metabolism, and inflammation. Olinciguat reduced blood pressure in normotensive and hypertensive rats. Olinciguat was cardioprotective in the Dahl rat salt-sensitive hypertensive heart failure model. In the rat ZSF1 model of diabetic nephropathy and metabolic syndrome, Olinciguat was renoprotective and associated with lower circulating glucose, cholesterol, and triglycerides. In a mouse TNFα-induced inflammation model, Olinciguat treatment was associated with lower levels of endothelial and leukocyte-derived soluble adhesion molecules. The pharmacological features of Olinciguat suggest that it may have broad therapeutic potential and that it may be suited for diseases that have both vascular and extravascular pathologies.