SAR-100842
目录号 : GC31785
SAR-100842 是一种有效的选择性 LPAR1 口服拮抗剂，用于治疗弥漫性皮肤系统性硬化症。
Cas No.:1195941-38-8
Sample solution is provided at 25 µL, 10mM.
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SAR-100842 is a potent, selective oral antagonist of the LPAR1, for diffuse cutaneous systemic sclerosis [1]. SAR-100842 is safe, moderately effective, and well-tolerated in patients [1].
SAR-100842(10 μM) showed weak inhibitory activity (25-30%) on the impact on Gαq signal transduction in an RH7777 cell line exogenously expressing the LPA1 receptor. SAR-100842 was able to fully inhibit the LPA driven Gαi signaling with an IC50 of 52.5 ± 12 nM. SAR-100842 (IC50 31 ± 8.5 nM) fully inhibited the LPA mediated G-protein signalling subsequently leads to recruitment and activation of β-arrestin. SAR-100842 showed a significant inhibition of Gα12/13 signalling at 1 and 10 μM in MeT-5A cell line [2]. 50 μM SAR-100842 reduced the migration of MDA-MD-231T cells through a collagen membrane to FBS and LPA chemoattractants, respectively. In 4T1-Luc2 cells 50 μM SAR-100842 reduced migration to FBS and LPA, respectively [3].
SAR-100842 (30 mg/kg BID) reversed significantly dermal thickness, inhibited myofibroblast differentiation and skin collagen content in the mouse model of bleomycin-induced skin fibrosis. SAR-100842 significantly reduced the expression of CXCL-1 and IL-13, associated with the TH-2 cytokine milieu found in Systemic Sclerosis (SSc) [4]. SAR-100842 has a half-life of 4.9 h and a Cmax of 5600 ng/mL after a 30 mg/kg oral dosing in mice [1].
References:
[1]. Allanore Y, Distler O, Jagerschmidt A, et al. Lysophosphatidic acid receptor 1 antagonist SAR100842 for patients with diffuse cutaneous systemic sclerosis: a double‐blind, randomized, eight‐week placebo‐controlled study followed by a sixteen‐week open‐label extension study[J]. Arthritis & Rheumatology, 2018, 70(10): 1634-1643.
[2]. Ellery J, Dickson L, Cheung T, et al. Identification of compounds acting as negative allosteric modulators of the LPA1 receptor[J]. European journal of pharmacology, 2018, 833: 8-15.
[3]. Brooks D, Zimmer A, Wakefield L, et al. Limited fibrosis accompanies triple-negative breast cancer metastasis in multiple model systems and is not a preventive target[J]. Oncotarget, 2018, 9(34): 23462.
[4]. Illiano S, Ledein L, Bidouard J P, et al. OP0228 Protective Effect of LPA1 and 3 Receptor Antagonism in Experimental Skin Fibrosis is Linked to LPA Activity in Dermal Fibroblasts of SSC Patients[J]. Annals of the Rheumatic Diseases, 2013, 72(Suppl 3): A129-A129.
SAR-100842 是一种有效的选择性 LPAR1 口服拮抗剂，用于治疗弥漫性皮肤系统性硬化症[1]。 SAR-100842 对患者安全、有效且耐受性良好[1]。
SAR-100842(10 μM) 对外源表达 LPA1 受体的 RH7777 细胞系中 Gαq 信号转导的影响显示出较弱的抑制活性 (25-30%)。 SAR-100842 能够完全抑制 LPA 驱动的 Gαi 信号，IC50 为 52.5 ± 12 nM。 SAR-100842 (IC50 31 ± 8.5 nM) 完全抑制 LPA 介导的 G 蛋白信号传导，随后导致 β-arrestin 的募集和激活。在 MeT-5A 细胞系 [2] 中，SAR-100842 在 1 和 10 μM 时显示出对 Gα12/13 信号的显着抑制。 50 μM SAR-100842 减少了 MDA-MD-231T 细胞通过胶原蛋白膜分别向 FBS 和 LPA 趋化剂的迁移。在 4T1-Luc2 细胞中，50 μM SAR-100842 分别减少了向 FBS 和 LPA 的迁移[3]。
在博来霉素诱导的皮肤纤维化小鼠模型中，SAR-100842（30 mg/kg BID）显着逆转真皮厚度，抑制肌成纤维细胞分化和皮肤胶原蛋白含量。 SAR-100842 显着降低了与系统性硬化症 (SSc) [4] 中发现的 TH-2 细胞因子环境相关的 CXCL-1 和 IL-13 的表达。 SAR-100842 在小鼠中口服 30 mg/kg 后的半衰期为 4.9 小时，Cmax 为 5600 ng/mL[1]。
| Cell experiment [1]: | |
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Cell lines |
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Preparation Method |
SAR-100842 were dissolved into 100% DMSO to 10 mM stock and further diluted in serum free media.cells were serum starved and incubated in vehicle or varying concentrations of drug for 24 hours. Lower wells contained DMEM with or without attractants (1-5% FBS or 5-10 µM LPA). 4T1-Luc2 or MDA-MB-231T cells were added to the upper wells at a concentration of 2×105 cells/mL in serum-free DMEM containing vehicle or SAR-100842 and incubated for 4 hours in a humidified chamber at 37⊿in 5% CO2. The top chamber was removed and the cells that had migrated to the bottom of the membrane were stained using Diff Quick Staining kit. Using an inverted brightfield microscope with a 10× objective, the number of cells that had migrated through the membrane was counted in three fields in the center of each filter. |
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Reaction Conditions |
0.5-50µM for 24, 48, 72 hours |
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Applications |
50 µM SAR-100842 reduced the migration of MDA-MD-231T cells through a collagen membrane by 1.92-fold and 3.15-fold to FBS and LPA chemoattractants, respectively. In 4T1-Luc2 cells 50 µM SAR-100842 reduced migration by 10.8-fold and 13.6-fold to FBS and LPA, respectively. |
| Animal experiment [1]: | |
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Animal models |
6-8 week old athymic nu/nu mice |
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Preparation Method |
Mice received 30 mg/kg SAR-100842 by oral gavage twice daily for the duration of the experiment. 6-8 week old athymic nu/nu mice received either 1.0 × 106 SKVO3 cells or 3.5 × 106 OVCAR5 cells in an intraperitoneal injection. On day two post cell injection, mice were randomized to three groups. Group one began vehicle on day 2, group two began 30 mg/kg SAR-100842 twice daily on day two for the duration of the experiment, and group three began 30 mg/kg SAR-100842 twice daily on day 10 for the duration of the experiment. On day 70 post cell injection all mice were euthanized and necropsied. Liver, abdominal lymph nodes or masses, omentum, peritoneum and any other organ suspected of harboring tumor were collected, fixed in 10% NBF and prepared for histological analysis. |
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Dosage form |
30 mg/kg twice daily, oral |
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Applications |
In the SKOV3 model treated early with SAR-100842, Only a weak reduction in diaphragm, kidney and lymph node metastases was evident ; none of these reductions were maintained in the group that started treatment on day 10 post-injection. For the OVCAR5 model, metastases were observed at day 70 post-injection on the omentum, liver, diaphragm, pancreas and peritoneum. Of these, SAR-100842 apparently reduced diaphragm tumor deposits, both surface and invasive, but was without significant effect in other locations. |
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References: [1]: Brooks D, Zimmer A, Wakefield L, et al. Limited fibrosis accompanies triple-negative breast cancer metastasis in multiple model systems and is not a preventive target[J]. Oncotarget, 2018, 9(34): 23462. |
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| Cas No. | 1195941-38-8 | SDF | |
| Canonical SMILES | O=C(C1(NC(C2=CC=C(OC)C(OCCC3=CC=CC(C)=C3)=C2)=O)CC4=C(C=CC=C4)C1)O | ||
| 分子式 | C27H27NO5 | 分子量 | 445.51 |
| 溶解度 | DMSO : ≥ 83.3 mg/mL (186.98 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 | 2.2446 mL | 11.2231 mL | 22.4462 mL |
| 5 mM | 0.4489 mL | 2.2446 mL | 4.4892 mL |
| 10 mM | 0.2245 mL | 1.1223 mL | 2.2446 mL |
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动物平均体重 | g | |
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动物数量 | 只 |
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| % DMSO % % Tween 80 % saline | ||||||||||
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2.
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Quality Control & SDS
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- Purity: >98.00%
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