Rosiptor (AQX-1125)
(Synonyms: 罗西普托,AQX-1125) 目录号 : GC32783
Rosiptor (AQX-1125) (AQX-1125) 是一种具有抗炎作用的选择性和口服活性磷酸酶 SHIP1 激活剂。 Rosiptor (AQX-1125) (AQX-1125) 在体外抑制 Akt 磷酸化、炎症介质产生和白细胞趋化性。
Cas No.:782487-28-9
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
Rosiptor is an activator of SH2-containing inositol-5'-phosphatase 1 (SHIP1).
Rosiptor is a small-molecule SHIP1 activator.The activating effect of Rosiptor on SHIP1 is 28% at 100 μM in the native enzyme but no effect of Rosiptor is observed when the SHIP1δC2 enzyme is used. Rosiptor induces a concentration-dependent decrease in Akt phosphorylation in MOLT-4 cells, while it fails to affect Akt phosphorylation in Jurkat cells. At 0.1 μM Rosiptor the inhibition amounts to an average of 34%, while at 10 μM the inhibition amounts to an average of 82% in two independent experiments. Rosiptor also induces a concentration-dependent decrease in the production of multiple pro-inflammatory mediators in this system, without affecting cell viability. Rosiptor dose dependently inhibits chemotaxis of most cell types at low micromolar concentrations independent of the chemotactic stimulus[1].
In female Sprague-Dawley rats, the single-dose pharmacokinetics of Rosiptor show that the increases in maximal plasma concentration (Cmax) and AUC0-∞ are dose-proportional at the lower end of the dosing regimen and greater than dose proportional at the higher doses. The oral bioavailability of Rosiptor in rats is 66 and 85% at 10 and 30 mg/kg respectively. Oral bioavailability of Rosiptor in dogs is 88 and 104% at 10 and 30 mg/kg respectively. High tissue concentrations of Rosiptor are detected, as compared to plasma concentrations, at each time point studied[1].
[1]. Stenton GR, et al. Characterization of AQX-1125, a small-molecule SHIP1 activator: Part 1. Effects on inflammatory cell activation and chemotaxis in vitro and pharmacokinetic characterization in vivo. Br J Pharmacol. 2013 Mar;168(6):1506-18.
| Cas No. | 782487-28-9 | SDF | |
| 别名 | 罗西普托,AQX-1125 | ||
| Canonical SMILES | C[C@@]([C@H]1CO)(CC[C@H](O)C1)[C@](CC[C@@]2(C)[C@@]3([H])CCC2=C)([H])[C@H]3CN | ||
| 分子式 | C20H35NO2 | 分子量 | 321.5 |
| 溶解度 | DMSO : 150 mg/mL (466.56 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 | 3.1104 mL | 15.5521 mL | 31.1042 mL |
| 5 mM | 0.6221 mL | 3.1104 mL | 6.2208 mL |
| 10 mM | 0.311 mL | 1.5552 mL | 3.1104 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。
AQX-1125, small molecule SHIP1 activator inhibits bleomycin-induced pulmonary fibrosis
Br J Pharmacol 2017 Sep;174(18):3045-3057.PMID:28658529DOI:10.1111/bph.13934.
Background and purpose: The phosphatase SHIP1 negatively regulates the PI3K pathway, and its predominant expression within cells of the haematopoietic compartment makes SHIP1 activation a novel strategy to limit inflammatory signalling generated through PI3K. AQX-1125 is the only clinical-stage, orally administered, SHIP1 activator. Here, we demonstrate the prophylactic and therapeutic effects of AQX-1125, in a mouse model of bleomycin-induced lung fibrosis. Experimental approach: For prophylactic evaluation, AQX-1125 (3, 10 or 30 mg·kg-1 ·d-1 , p.o.) or dexamethasone (1 mg·kg-1 ·d-1 , i.p.) were given to CD-1 mice starting 3 days before intratracheal administration of bleomycin (0.1 IU per mouse) and continued daily for 7 or 21 days. Therapeutic potentials of AQX-1125 (3, 10 or 30 mg·kg-1 ·d-1 , p.o.) or pirfenidone (90 mg·kg-1 ·d-1 , p.o.) were assessed by initiating treatment 13 days after bleomycin instillation and continuing until day 28. Key results: Given prophylactically, AQX-1125 (10 and 30 mg·kg-1 ) reduced histopathological changes in lungs, 7 and 21 days following bleomycin-induced injury. At the same doses, AQX-1125 reduced the number of total leukocytes, neutrophil activity, TGF-β immunoreactivity and soluble collagen in lungs. Administered therapeutically, AQX-1125 (10 and 30 mg·kg-1 ) improved lung histopathology, cellular infiltration and reduced lung collagen content. At 30 mg·kg-1 , the effects of AQX-1125 were similar to those of pirfenidone (90 mg·kg-1 ) with corresponding improvements in disease severity. Conclusions and implications: AQX-1125 prevented bleomycin-induced lung injury during the inflammatory and fibrotic phases. AQX-1125, given therapeutically, modified disease progression and improved survival, as effectively as pirfenidone.
SHIP1 Activator AQX-1125 Regulates Osteogenesis and Osteoclastogenesis Through PI3K/Akt and NF-κb Signaling
Front Cell Dev Biol 2022 Apr 4;10:826023.PMID:35445030DOI:10.3389/fcell.2022.826023.
With the worldwide aging population, the prevalence of osteoporosis is on the rise, particularly the number of postmenopausal women with the condition. However, the various adverse side effects associated with the currently available treatment options underscore the need to develop novel therapies. In this study, we investigated the use of AQX-1125, a novel clinical-stage activator of inositol phosphatase-1 (SHIP1), in ovariectomized (OVX) mice, identifying a protective role. We then found that the effect was likely due to increased osteogenesis and mineralization and decreased osteoclastogenesis caused by AQX-1125 in a time- and dose-dependent manner. The effect against OVX-induced bone loss was identified to be SHIP1-dependent as pretreatment of BMSCs and BMMs with SHIP1 RNAi could greatly diminish the osteoprotective effects. Furthermore, SHIP1 RNAi administration in vivo induced significant bone loss and decreased bone mass. Mechanistically, AQX-1125 upregulated the expression level and activity of SHIP1, followed upregulating the phosphorylation levels of PI3K and Akt to promote osteoblast-related gene expressions, including Alp, cbfa1, Col1a1, and osteocalcin (OCN). NF-κB signaling was also inhibited through suppression of the phosphorylation of IκBα and P65 induced by RANKL, resulting in diminished osteoclastogenesis. Taken together, our results demonstrate that AQX-1125 may be a promising candidate for preventing and treating bone loss.
Synthetic studies on the indane SHIP1 agonist AQX-1125
Org Biomol Chem 2022 May 18;20(19):4016-4020.PMID:PMC9153081DOI:10.1039/d2ob00555g.
AQX-1125 is an indane based SHIP1 agonist that has been evaluated in the clinic for the treatment of bladder pain syndrome/interstitial cystitis. To support our own studies on SHIP1 agonists as potential treatments for IBD and Crohn's disease, a new synthetic route to the SHIP1 agonist AQX-1125 has been developed. This sequence utilizes a hydroxy-acid intermediate which allows for ready differentiation of the C6 and C7 positions. The role of the C17 alkene in the biological activity of the system is also investigated, and this functional group is not required for SHIP1 agonist activity. While AQX-1125 shows SHIP1 agonist activity in enzyme assays, it does not show activity in cell based assays similar to other SHIP1 agonists, which limits the utility of this molecule.
The effects of the novel SHIP1 activator AQX-1125 on allergen-induced responses in mild-to-moderate asthma
Clin Exp Allergy 2014 Sep;44(9):1146-53.PMID:25040039DOI:10.1111/cea.12370.
Background: SH2-containing inositol-5'-phosphatase 1 (SHIP1) is an endogenous inhibitor of the phosphoinositide-3-kinase pathway that is involved in the activation and chemotaxis of inflammatory cells. AQX-1125 is a first-in-class, oral SHIP1 activator with a novel anti-inflammatory mode of action. Objective: To evaluate the effects of AQX-1125 on airway responses to allergen challenge in mild-to-moderate asthmatic patients. Methods: A randomized, double-blind, placebo-controlled, two-way crossover study was performed in 22 steroid-naïve mild-to-moderate asthmatics with a documented late-phase response to inhaled allergen (LAR). AQX-1125 (450 mg daily) or placebo was administered orally for 7 days. Allergen challenge was performed on day 6 (2 h postdose), followed by methacholine challenge (day 7), and induced sputum collection and fractional exhaled nitric oxide (FeNO). Results: AQX-1125 significantly attenuated the late-phase response compared with placebo (FEV1 4-10 h: mean difference 150 mL, 20%; P = 0.027) and significantly increased the minimum FEV1 during LAR (mean difference 180 mL; P = 0.014). AQX-1125 had no effect on the early-phase response. AQX-1125 showed a trend in reduction of sputum eosinophils, neutrophils and macrophages although this did not achieve significance as there were only 11 paired samples for analysis. There was no effect on methacholine responsiveness or FeNO. Pharmacokinetic data showed AQX-1125 was rapidly absorbed with geometric mean Cmax and AUC0-24 h values of 1417 ng/mL and 16 727 h ng/mL, respectively. AQX-1125 was well tolerated, but mild GI side-effects (dyspepsia, nausea and abdominal pain) were described in 4/22 subjects on active treatment. These side-effects were mild self-limiting, required no further treatment and did not lead to discontinuation of therapy. Conclusion and clinical relevance: AQX-1125, a novel oral SHIP1 activator, significantly reduces the late response to allergen challenge, with a trend to reduce airway inflammation. AQX-1125 was safe and well tolerated and merits further investigation in inflammatory disorders.
Characterization of AQX-1125, a small-molecule SHIP1 activator: Part 2. Efficacy studies in allergic and pulmonary inflammation models in vivo
Br J Pharmacol 2013 Mar;168(6):1519-29.PMID:23121409DOI:10.1111/bph.12038.
Background: The efficacy of AQX-1125, a small-molecule SH2-containing inositol-5'-phosphatase 1 (SHIP1) activator and clinical development candidate, is investigated in rodent models of inflammation. Experimental approach: AQX-1125 was administered orally in a mouse model of passive cutaneous anaphylaxis (PCA) and a number of rodent models of respiratory inflammation including: cigarette smoke, LPS and ovalbumin (OVA)-mediated airway inflammation. SHIP1 dependency of the AQX-1125 mechanism of action was investigated by comparing the efficacy in wild-type and SHIP1-deficient mice subjected to an intrapulmonary LPS challenge. Results: AQX-1125 exerted anti-inflammatory effects in all of the models studied. AQX-1125 decreased the PCA response at all doses tested. Using bronchoalveolar lavage (BAL) cell counts as an end point, oral or aerosolized AQX-1125 dose dependently decreased the LPS-mediated pulmonary neutrophilic infiltration at 3-30 mg kg⁻¹ and 0.15-15 μg kg⁻¹ respectively. AQX-1125 suppressed the OVA-mediated airway inflammation at 0.1-10 mg kg⁻¹. In the smoke-induced airway inflammation model, AQX-1125 was tested at 30 mg kg⁻¹ and significantly reduced the neutrophil infiltration of the BAL fluid. AQX-1125 (10 mg kg⁻¹) decreased LPS-induced pulmonary neutrophilia in wild-type mice but not in SHIP1-deficient mice. Conclusions: The SHIP1 activator, AQX-1125, suppresses leukocyte accumulation and inflammatory mediator release in rodent models of pulmonary inflammation and allergy. As shown in the mouse model of LPS-induced lung inflammation, the efficacy of the compound is dependent on the presence of SHIP1. Pharmacological SHIP1 activation may have clinical potential for the treatment of pulmonary inflammatory diseases.