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Upamostat (WX-671) Sale

(Synonyms: WX-671) 目录号 : GC32882

Upamostat (WX-671), a novel serine protease urokinase (uPA) inhibitor by inhibiting the urokinase-type plasminogen activator (uPA) system.

Upamostat (WX-671) Chemical Structure

Cas No.:590368-25-5

规格 价格 库存 购买数量
10mM (in 1mL DMSO)
¥2,743.00
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5mg
¥1,980.00
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10mg
¥3,150.00
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25mg
¥6,120.00
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50mg
¥9,450.00
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实验参考方法

Animal experiment:

Rats[3] Five 9-week old Sprague-Dawley rats are administered a single intravenous injection of 2 mg/kg of Upamostat. Upamostat is dissolved in a mixture of normal saline, dimethylacetamide, polyethylene glycol 400 and DMSO (3:3:3:1). Blood samples (0.15 mL) are taken serially for up to 10 h after drug administration and collected in heparinized centrifuge tubes. After centrifugation at 13,200 rpm for 10 min, the plasma samples are analyzed[3].

References:

[1]. Heinemann V, et al. Phase II randomised proof-of-concept study of the urokinase inhibitor upamostat (WX-671) in combination with gemcitabine compared with gemcitabine alone in patients with non-resectable, locally advanced pancreatic cancer. Br J Cancer. 2013 Mar 5;108(4):766-70.
[2]. Froriep D, et al. Activation of the anti-cancer agent upamostat by the mARC enzyme system. Xenobiotica. 2013 Sep;43(9):780-4.
[3]. Park C, et al. HPLC-MS/MS analysis of mesupron and its application to a pharmacokinetic study in rats. J Pharm Biomed Anal. 2018 Feb 20;150:39-42.

产品描述

Upamostat (WX-671), a novel serine protease urokinase (uPA) inhibitor by inhibiting the urokinase-type plasminogen activator (uPA) system.

Chemical Properties

Cas No. 590368-25-5 SDF
别名 WX-671
Canonical SMILES O=C(N1CCN(C([C@@H](NS(=O)(C2=C(C(C)C)C=C(C(C)C)C=C2C(C)C)=O)CC3=CC=CC(C(NO)=N)=C3)=O)CC1)OCC
分子式 C32H47N5O6S 分子量 629.81
溶解度 DMSO : ≥ 250 mg/mL (396.95 mM) 储存条件 Store at -20°C
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1 mM 1.5878 mL 7.9389 mL 15.8778 mL
5 mM 0.3176 mL 1.5878 mL 3.1756 mL
10 mM 0.1588 mL 0.7939 mL 1.5878 mL
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Research Update

Phase II randomised proof-of-concept study of the urokinase inhibitor Upamostat (WX-671) in combination with gemcitabine compared with gemcitabine alone in patients with non-resectable, locally advanced pancreatic cancer

Br J Cancer 2013 Mar 5;108(4):766-70.PMID:23412098DOI:10.1038/bjc.2013.62.

Background: To evaluate the efficacy and tolerability of the urokinase plasminogen activator (uPA) inhibitor upamostat in combination with gemcitabine in locally advanced pancreatic adenocarcinoma (LAPC). Methods: Within a prospective multicenter study, LAPC patients were randomly assigned to receive 1000 mg m(-2) of gemcitabine IV weekly either alone (arm A) or in combination with 200 mg (arm B) or 400 mg (arm C) oral upamostat daily. Efficacy endpoints of this proof-of-concept study included response rate, time to first metastasis, progression-free and overall survival (OS). Results: Of the 95 enroled patients, 85 were evaluable for response and 93 for safety. Median OS was 12.5 months (95% CI 8.2-18.2) in arm C, 9.7 months (95% CI 8.4-17.1) in arm B and 9.9 months (95% CI 7.4-12.1) in arm A; corresponding 1-year survival rates were 50.6%, 40.7% and 33.9%, respectively. More patients achieved a partial remission (confirmed responses by RECIST) with upamostat combination therapy (arm C: 12.9%; arm B: 7.1%; arm A: 3.8%). Overall, only 12 patients progressed by developing detectable distant metastasis (arm A: 4, arm B: 6, arm C: 2). The most common adverse events considered to be related to upamostat were asthenia, fever and nausea. Conclusion: In this proof-of-concept study targeting the uPA system in LAPC, the addition of upamostat to gemcitabine was tolerated well; similar survival results were observed for the three treatment arms.

Activation of the anti-cancer agent Upamostat by the mARC enzyme system

Xenobiotica 2013 Sep;43(9):780-4.PMID:23379481DOI:10.3109/00498254.2013.767481.

Upamostat (Mesupron®) is a new small molecule serine protease inhibitor. The drug candidate was developed to inhibit the urokinase-type plasminogen activator (uPA) system, which plays a major role in tumor invasion and metastasis. Upamostat is currently in clinical development as an anti-metastatic and non-cytotoxic agent against pancreatic and breast cancer. Upamostat is the orally available amidoxime- (i.e. hydroxyamidine-) prodrug of the pharmacologically active form, WX-UK1. In this study, the reductive enzymatic activation of Upamostat to its corresponding amidine WX-UK1 was analyzed. The recently discovered molybdenum enzyme "mitochondrial Amidoxime Reducing Component" (mARC) catalyses together with its electron transport proteins cytochrome b₅ and NADH cytochrome b₅ reductase the reduction of N-hydroxylated prodrugs. In vitro biotransformation assays with porcine subcellular fractions and the reconstituted human enzymes demonstrate an mARC-dependent N-reduction of Upamostat.

Reducing tumor growth and angiogenesis using a triple therapy measured with Contrast-enhanced ultrasound (CEUS)

BMC Cancer 2015 May 8;15:373.PMID:25947947DOI:10.1186/s12885-015-1333-7.

Background: To evaluate the in vivo response by detecting the anti-angiogenic and invasion-inhibiting effects of a triple-combination-therapy in an experimental-small-animal-squamous-cell-carcinoma-model using the "flash-replenishment" (FR) method to assess tissue hemodynamics via contrast-enhanced-ultrasound (CEUS). Methods: Human hypopharynx-carcinoma-cells were subcutaneously injected into the left flank of 22-female-athymic-nude-rats. After seven days of subcutaneous tumor growth, FR-measurements were performed on each rat. Treatment-group and control-group were treated every day for a period of one week, with the treatment-group receiving solvents containing a triple therapy of Upamostat®, Celecoxib® and Ilomastat® and the control-group solvents only. On day seven, follow-up measurements were performed using the same measurement protocol to assess the effects of the triple therapy. VueBox® was used to quantify the kinetic parameters and additional immunohistochemistry analyses were performed for comparison with and validation of the CEUS results against established methods (Proliferation/Ki-67, vascularization/CD31, apoptosis/caspase3). Results: Compared to the control-group, the treatment-group that received the triple-therapy resulted in a reduction of tumor growth by 48.6% in size. Likewise, the immunohistochemistry results showed significant decreases in tumor proliferation and vascularization in the treatment-group in comparison to the control-group of 26%(p ≤ 0.05) and 32.2%(p ≤ 0.05) respectively. Correspondingly, between the baseline and follow-up measurements, the therapy-group was associated with a significant(p ≤ 0.01) decrease in the relative-Blood-Volume(rBV) in both the whole tumor(wt) and hypervascular tumor(ht) areas (p ≤ 0.01), while the control-group was associated with a significant (p ≤ 0.01) increase of the rBV in the wt area and a non-significant increase (p ≤ 0.16) in the ht area. The mean-transit-time (mTT) of the wt and the ht areas showed a significant increase (p ≤ 0.01) in the follow-up measurements in the therapy group. Conclusion: The triple-therapy is feasible and effective in reducing both tumor growth and vascularization. In particular, compared with the placebo-group, the triple-therapy-group resulted in a reduction in tumor growth of 48.6% in size when assessed by CEUS and a significant reduction in the number of vessels in the tumor of 32% as assessed by immunohistochemistry. As the immunohistochemistry supports the CEUS findings, CEUS using the "flash replenishment"(FR) method appears to provide a useful assessment of the anti-angiogenic and invasion-inhibiting effects of a triple combination therapy.

DCE-MRI biomarkers for monitoring an anti-angiogenic triple combination therapy in experimental hypopharynx carcinoma xenografts with immunohistochemical validation

Acta Radiol 2015 Mar;56(3):294-303.PMID:24609871DOI:10.1177/0284185114527444.

Background: Novel anti-angiogenic treatments are increasingly complementing established cancer therapy strategies in head and neck tumors. Contrast-enhanced magnetic resonance imaging (MRI) can be applied for early and non-invasive therapy monitoring by non-invasive quantitative assessment of tumor microcirculation as in vivo imaging biomarkers of therapy response. Purpose: To monitor the anti-angiogenic effects of a novel combination therapy on experimental head and neck squamous cell carcinomas (HNSCC) with dynamic contrast-enhanced (DCE)-MRI. Material and methods: Athymic rats (n = 18) with subcutaneous HNSCC xenografts were investigated by DCE-MRI before and after 7 days of a daily triple therapy regimen combining the COX-II-inhibitor celecoxib, the matrix-metalloproteinase-inhibitor GM6001, and the uPA-inhibitor Upamostat. Quantitative measurements of tumor blood flow (tBF), tumor blood volume (tBV), and permeability-surface area product (PS) were calculated and validated by immunohistochemistry. Results: Mean tBF and tBV in triple-therapy animals decreased significantly from day 0 to day 7 (tBF, 41.0 ± 14.2 to 20.4 ± 5.7 mL/100 mL/min; P < 0.01; tBV, 17.7 ± 3.9 to 7.5 ± 3.3%; P < 0.01). No significant effects on PS were observed in either group (P > 0.05). Immunohistochemical analysis showed a significantly lower tumor vascularity in the therapy group than in the control group (CD31), significantly fewer Ki-67+ proliferating tumor cells and significantly more Capase-3+ apoptotic tumor cells (P < 0.05). Significant (P < 0.05) correlations were observed between tBF/tBV and CD31 (tBF, r = 0.84; tBV, r = 0.70), tBV and Ki-67 (r = 0.62), as well as tBF and caspase-3 (r = -0.64). Conclusion: DCE-MRI may be a suitable tool for the non-invasive monitoring of the anti-vascular effects of this innovative triple therapy regimen with potential for clinical translation.

A randomized, placebo-controlled pilot study of Upamostat, a host-directed serine protease inhibitor, for outpatient treatment of COVID-19

Int J Infect Dis 2023 Mar;128:148-156.PMID:36549549DOI:10.1016/j.ijid.2022.12.003.

Objectives: We performed a pilot study of Upamostat, a serine protease inhibitor, in outpatients with symptomatic COVID-19 before a pivotal trial. Methods: SARS-CoV-2 patients with ≥2 moderate-severe symptoms onset within 5 days were randomized to oral Upamostat 200 or 400 mg or placebo daily for 14 days. Patients completed COVID-19 symptom questionnaires daily for 28 days, then thrice weekly for 4 weeks, and underwent physical and laboratory examinations periodically. Results: A total of 61 patients enrolled of which 20 received a placebo or Upamostat 200 mg daily; 21 received Upamostat 400 mg daily. Treatment was well tolerated; only one patient (Upamostat 400) reported a drug-related adverse event, mild skin rash; no patient discontinued owing to a drug-related adverse event. The median time to a sustained recovery from severe symptoms was 8, 4, and 3 days for the three treatment groups, respectively. New severe symptoms developed in 20% of the placebo group vs 2.4% in the combined Upamostat groups, (P = 0.036). Three placebo patients (15%) versus no Upamostat patients were hospitalized for worsening COVID (P= 0.03). The mean d-dimer level remained constant in placebo patients but decreased by 38% and 48% in Upamostat 200 and 400 patients, respectively. Conclusion: Upamostat was well tolerated, shortened recovery time, and decreased new severe symptoms and hospitalization.