PARP (IC50 =120 μM)

体外活性：BGP-15 (200 μM) 可防止甲磺酸伊马替尼诱导的氧化损伤，减弱高能磷酸盐的消耗，通过阻止 p38 MAP 激酶和 JNK 激活来改变甲磺酸伊马替尼的信号传导作用，并诱导Akt 和 GSK-3beta。细胞分析：先前的研究表明，200 μM 的 BGP-15 可以防止伊马替尼诱导的氧化损伤，减弱高能磷酸盐的消耗，通过阻止 p38 MAP 激酶和 JNK 激活来改变伊马替尼的信号传导作用，并诱导Akt 和 GSK-3β 磷酸化。

BGP-15（15 mg/kg，口服）不会改善老年 mdx 小鼠的骨骼肌病理学。在大鼠模型中，BGP-15 治疗 10 天可极大改善膈肌纤维功能（约 100%），尽管它不能逆转膈肌萎缩。该治疗还提供针对与 HSP72 诱导和 PARP-1 抑制相关的肌球蛋白 PTM 的保护，从而改善线粒体功能和含量。根据形态学、心脏功能和心电图参数，BGP-15（每天 15 毫克/千克，盐水）治疗对 Ntg 小鼠或正常成年野生型小鼠的独立群体没有影响。 BGP-15 治疗可减轻心房大小和肺重量的增加。 BGP-15 治疗能够预防或减少心律失常的发作。 BGP-15 治疗与 HF+AF 模型中 PR 间期缩短相关。

在Langendorff心脏灌注系统中研究了O-（3-哌啶-2-羟基-1-丙基）烟酰胺肟（BGP-15）对缺血再灌注损伤的保护作用。为了了解心脏保护的分子机制，研究了BGP-15对缺血再灌注诱导的活性氧（ROS）形成、脂质过氧化单链DNA断裂形成、NAD（+）分解代谢和内源性ADP核糖基化反应的影响。这些研究表明，BGP-15显著降低了再灌注心脏中乳酸脱氢酶、肌酸激酶和天冬氨酸转氨酶的渗漏，并降低了NAD（+）分解代谢的速率。此外，BGP-15显著降低了缺血再灌注诱导的核聚ADP核糖聚合酶（PARP）的自身ADP核糖基化和内质网伴侣GRP78的单ADP核糖基基化。这些数据增加了BGP-15可能对PARP具有直接抑制作用的可能性。这一假设在分离的酶上进行了测试，动力学分析显示混合型（非竞争性）抑制，K（i）=57+/-6μM。此外，BGP-15降低了再灌注心脏中ROS、脂质过氧化和单链DNA断裂的水平。这些数据表明，PARP可能是BGP-15的一个重要分子靶标，并且BGP-15通过抑制PARP活性来降低心脏缺血再灌注过程中的ROS水平和细胞损伤[4]。

根据之前的一项研究，200 μM 的 BGP-15 可以防止伊马替尼引起的氧化损伤，减少高能磷酸盐的损失，通过阻止 JNK 和 p38 MAP 激酶的激活来改变伊马替尼信号的方式，以及磷酸化 GSK -3β 和 Akt。

Male adult HF+AF and Ntg mice, who are approximately 4 months old, are given BGP-15 (15 mg/kg daily in saline) or left untreated (oral gavage with saline or no gavage) for 4 weeks. In the HF+AF model, gavage with saline has no effect on morphological or functional parameters. Thus, mice receiving saline injection and mice left untreated (no gavage) are grouped together and referred to as HF+AF control. ECG and echocardiography scans are carried out both before and after therapy.

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Experimental protocols[3]
Protocol 1: Adult (~4 month) male HF+AF and Ntg mice were administered with BGP-15 (15 mg kg−1 per day in saline, N-Gene Research Laboratories) for 4 weeks by oral gavage or remained untreated (oral gavage with saline or no gavage). Gavage with saline had no effect on morphological or functional parameters in the HF+AF model (Supplementary Fig. 3). Therefore, untreated mice (no gavage) and mice administered saline are combined and referred to as HF+AF control. Echocardiography and ECG studies were performed before and after treatment.[3]
Protocol 2: To determine whether BGP-15 provided protection via HSP70, BGP-15 (15 mg kg−1 per day, oral gavage) was administered to adult (~14 weeks) male and female HF+AF mice deficient for HSP70 (HF+AF-HSP70 KO) for 4 weeks.[3]
Protocol 3: To assess whether an increase in HSP70 could mediate protection in the HF+AF model, male HF+AF mice overexpressing HSP70 (HF+AF-HSP70 Tg) were generated and characterized at ~12–13 weeks.[3]
Protocol 4: To examine whether overexpression of IGF1R in the heart could provide protection in the HF+AF model, male HF+AF mice overexpressing IGF1R (HF+AF-IGF1R Tg) were generated and characterized at ~16–17 weeks.[3]
Protocol 5: To determine whether IGF1R could mediate protection in the HF+AF model independent of HSP70, male and female HF+AF-IGF1R Tg-HSP70 KO mice were generated and characterized at ~11 weeks.[3]
Protocol 6: To examine whether BGP-15 had the capacity to provide protection in an additional model with HF and AF, 11- to 12-month-old male MURC Tg were administered with BGP-15 (15 mg kg−1 per day, oral gavage) or saline for 4 weeks.[3]

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To assess whether BGP-15 administration could confer effects on an already established dystrophic pathology, 20-week-old mdx and 8-week-old dko mice were administered BGP-15 (15 mg/kg in 0.9% sterile saline; N-Gene Research Laboratories Inc., New York, NY) daily via oral gavage for 4 (dko) or 5 (mdx) weeks. Age-matched vehicle-treated dystrophic and healthy wild-type control (C57BL/10) mice received an equivalent volume of 0.9% sterile saline via daily oral gavage. Because of the severity of the dko phenotype, a shorter treatment period was used with a significant number of mice reaching humane end point criteria (ie, kyphosis score of 5 and sustained 15% loss of body mass) after 12 weeks of age. The average lifespan of mice in our dko colony was approximately 14 to 15 weeks, with the severity of the dystrophic pathology at 8 weeks of age (when treatment commenced) indicated by an average kyphosis score of 2.5. The kyphosis score indicates the severity of spinal curvature on palpation of conscious mice and ranked 1 to 5, with 1 indicating no spinal deformity and 5 being the most severe. To assess the effect of BGP-15 administration as a preventive treatment for the dystrophic cardiomyopathy and to confirm previous findings on skeletal muscles of young mice,14 4-week-old dko mice were administered BGP-15 (15 mg/kg in 0.9% sterile saline daily via oral gavage) for 5 to 6 weeks, with other groups of aged-matched dko and C57BL/10 mice treated similarly with vehicle only. Because BGP-15 is a hydroxylamine derivative that affects only stressed cells, a group of C57BL/10 mice treated with BGP-15 was not included.10,14,34 Previous studies investigating BGP-15 effects on skeletal muscle and heart observed no morphological or functional changes in either tissue, in wild-type mice after long-term treatment.14,34 To assess Hsp72 induction via BGP-15, 4- and 10-week-old dko mice and age-matched C57BL/10 mice were administered a single bolus of BGP-15 (15 mg/kg) via oral gavage, and the tibialis anterior (TA) muscles, heart, and diaphragm were excised 6 hours later, frozen in liquid nitrogen, and stored at −80°C for later analyses.[1]

[1]. BGP-15 Improves Aspects of the Dystrophic Pathology in mdx and dko Mice with Differing Efficacies in Heart and Skeletal Muscle. Am J Pathol. 2016 Dec;186(12):3246-3260.

[2]. The chaperone co-inducer BGP-15 alleviates ventilation-induced diaphragm dysfunction. Sci Transl Med. 2016 Aug 3;8(350):350ra10.

[3]. The small-molecule BGP-15 protects against heart failure and atrial fibrillation in mice. Nat Commun. 2014 Dec 9;5:5705.

[4]. Improvement of insulin sensitivity by a novel drug candidate, BGP-15, in different animal studies. Metab Syndr Relat Disord. 2014 Mar;12(2):125-31.

[5]. BGP-15, a PARP-inhibitor, prevents imatinib-induced cardiotoxicity by activating Akt and suppressing JNK and p38 MAP kinases. Mol Cell Biochem. 2012 Jun;365(1-2):129-37.

[6]. BGP-15, a nicotinic amidoxime derivate protecting heart from ischemia reperfusion injury through modulation of poly(ADP-ribose) polymerase. Biochem Pharmacol. 2000 Apr 15;59(8):937-45.

Duchenne muscular dystrophy is a severe and progressive striated muscle wasting disorder that leads to premature death from respiratory and/or cardiac failure. We have previously shown that treatment of young dystrophic mdx and dystrophin/utrophin null (dko) mice with BGP-15, a coinducer of heat shock protein 72, ameliorated the dystrophic pathology. We therefore tested the hypothesis that later-stage BGP-15 treatment would similarly benefit older mdx and dko mice when the dystrophic pathology was already well established. Later stage treatment of mdx or dko mice with BGP-15 did not improve maximal force of tibialis anterior (TA) muscles (in situ) or diaphragm muscle strips (in vitro). However, collagen deposition (fibrosis) was reduced in TA muscles of BGP-15-treated dko mice but unchanged in TA muscles of treated mdx mice and diaphragm of treated mdx and dko mice. We also examined whether BGP-15 treatment could ameliorate aspects of the cardiac pathology, and in young dko mice it reduced collagen deposition and improved both membrane integrity and systolic function. These results confirm BGP-15's ability to improve aspects of the dystrophic pathology but with differing efficacies in heart and skeletal muscles at different stages of the disease progression. These findings support a role for BGP-15 among a suite of pharmacological therapies for Duchenne muscular dystrophy and related disorders.[1]

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Ventilation-induced diaphragm dysfunction (VIDD) is a marked decline in diaphragm function in response to mechanical ventilation, which has negative consequences for individual patients' quality of life and for the health care system, but specific treatment strategies are still lacking. We used an experimental intensive care unit (ICU) model, allowing time-resolved studies of diaphragm structure and function in response to long-term mechanical ventilation and the effects of a pharmacological intervention (the chaperone co-inducer BGP-15). The marked loss of diaphragm muscle fiber function in response to mechanical ventilation was caused by posttranslational modifications (PTMs) of myosin. In a rat model, 10 days of BGP-15 treatment greatly improved diaphragm muscle fiber function (by about 100%), although it did not reverse diaphragm atrophy. The treatment also provided protection from myosin PTMs associated with HSP72 induction and PARP-1 inhibition, resulting in improvement of mitochondrial function and content. Thus, BGP-15 may offer an intervention strategy for reducing VIDD in mechanically ventilated ICU patients.[2]

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Heart failure (HF) and atrial fibrillation (AF) share common risk factors, frequently coexist and are associated with high mortality. Treatment of HF with AF represents a major unmet need. Here we show that a small molecule, BGP-15, improves cardiac function and reduces arrhythmic episodes in two independent mouse models, which progressively develop HF and AF. In these models, BGP-15 treatment is associated with increased phosphorylation of the insulin-like growth factor 1 receptor (IGF1R), which is depressed in atrial tissue samples from patients with AF. Cardiac-specific IGF1R transgenic overexpression in mice with HF and AF recapitulates the protection observed with BGP-15. We further demonstrate that BGP-15 and IGF1R can provide protection independent of phosphoinositide 3-kinase-Akt and heat-shock protein 70; signalling mediators often defective in the aged and diseased heart. As BGP-15 is safe and well tolerated in humans, this study uncovers a potential therapeutic approach for HF and AF.[3]

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Background: Insulin resistance has been recognized as the most significant predictor of further development of type 2 diabetes mellitus (T2DM). Here we investigated the effect of a heat shock protein (HSP) co-inducer, BGP-15, on insulin sensitivity in different insulin-resistant animal models and compared its effect with insulin secretagogues and insulin sensitizers. Methods: Insulin sensitivity was assessed by the hyperinsulinemic euglycemic glucose clamp technique in normal and cholesterol-fed rabbits and in healthy Wistar and Goto-Kakizaki (GK) rats in dose-ranging studies. We also examined the effect of BGP-15 on streptozotocin-induced changes in the vasorelaxation of the aorta in Sprague-Dawley rats. Results: BGP-15 doses of 10 and 30 mg/kg increased insulin sensitivity by 50% and 70%, respectively, in cholesterol-fed but not in normal rabbits. After 5 days of treatment with BGP-15, the glucose infusion rate was increased in a dose-dependent manner in genetically insulin-resistant GK rats. The most effective dose was 20 mg/kg, which showed a 71% increase in insulin sensitivity compared to control group. Administration of BGP-15 protected against streptozotocin-induced changes in vasorelaxation, which was similar to the effect of rosiglitazone. Conclusion: Our results indicate that the insulin-sensitizing effect of BGP-15 is comparable to conventional insulin sensitizers. This might be of clinical utility in the treatment of T2DM.[4]

C14H24CL2N4O2

351.27

278.174

C, 60.41; H, 7.97; N, 20.13; O, 11.50

66611-38-9

9817104

Light yellow to yellow solid powder

1.203

81.47

2

5

6

20

306

0

OC(CN1CCCCC1)CONC(C1=CC=CN=C1)=N

MVLOQULXIYSERZ-UHFFFAOYSA-N

InChI=1S/C14H22N4O2/c15-14(12-5-4-6-16-9-12)17-20-11-13(19)10-18-7-2-1-3-8-18/h4-6,9,13,19H,1-3,7-8,10-11H2,(H2,15,17)

N'-(2-hydroxy-3-piperidin-1-ylpropoxy)pyridine-3-carboximidamide

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

注意： 请将本产品存放在密封且受保护的环境中，避免吸湿/受潮。

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

注意: 如下所列的是一些常用的体内动物实验溶解配方，主要用于溶解难溶或不溶于水的产品（水溶度<1 mg/mL）。 建议您先取少量样品进行尝试，如该配方可行，再根据实验需求增加样品量。

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注射用配方1: DMSO : Tween 80： Saline = 10 : 5 : 85 (如： 100 μL DMSO → 50 μL Tween 80 → 850 μL Saline)
*生理盐水/Saline的制备：将0.9g氯化钠/NaCl溶解在100 mL ddH ₂ O中，得到澄清溶液。
注射用配方 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (如： 100 μL DMSO → 400 μL PEG300 → 50 μL Tween 80 → 450 μL Saline)
注射用配方 3: DMSO : Corn oil = 10 : 90 (如： 100 μL DMSO → 900 μL Corn oil)
示例: 以注射用配方 3 (DMSO : Corn oil = 10 : 90) 为例说明, 如果要配制 1 mL 2.5 mg/mL的工作液, 您可以取 100 μL 25 mg/mL 澄清的 DMSO 储备液，加到 900 μL Corn oil/玉米油中, 混合均匀。

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注射用配方 4: DMSO : 20% SBE-β-CD in Saline = 10 : 90 [如：100 μL DMSO → 900 μL (20% SBE-β-CD in Saline)]
*20% SBE-β-CD in Saline的制备（4°C，储存1周）：将2g SBE-β-CD (磺丁基-β-环糊精) 溶解于10mL生理盐水中，得到澄清溶液。
注射用配方 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (如： 500 μL 2-Hydroxypropyl-β-cyclodextrin (羟丙基环胡精)→ 500 μL Saline)
注射用配方 6: DMSO : PEG300 : Castor oil : Saline = 5 : 10 : 20 : 65 (如： 50 μL DMSO → 100 μL PEG300 → 200 μL Castor oil → 650 μL Saline)
注射用配方 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (如： 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
注射用配方 8: 溶解于Cremophor/Ethanol (50 : 50), 然后用生理盐水稀释。
注射用配方 9: EtOH : Corn oil = 10 : 90 (如： 100 μL EtOH → 900 μL Corn oil)
注射用配方 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (如： 100 μL EtOH → 400 μL PEG300 → 50 μL Tween 80 → 450 μL Saline)

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口服配方 1: 悬浮于0.5% CMC Na (羧甲基纤维素钠)
口服配方 2: 悬浮于0.5% Carboxymethyl cellulose (羧甲基纤维素)
示例: 以口服配方 1 (悬浮于 0.5% CMC Na)为例说明, 如果要配制 100 mL 2.5 mg/mL 的工作液, 您可以先取0.5g CMC Na并将其溶解于100mL ddH2O中，得到0.5%CMC-Na澄清溶液；然后将250 mg待测化合物加到100 mL前述 0.5%CMC Na溶液中，得到悬浮液。

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口服配方 3: 溶解于 PEG400 (聚乙二醇400)
口服配方 4: 悬浮于0.2% Carboxymethyl cellulose (羧甲基纤维素)
口服配方 5: 溶解于0.25% Tween 80 and 0.5% Carboxymethyl cellulose (羧甲基纤维素)
口服配方 6: 做成粉末与食物混合

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注意: 以上为较为常见方法，仅供参考， InvivoChem并未独立验证这些配方的准确性。具体溶剂的选择首先应参照文献已报道溶解方法、配方或剂型，对于某些尚未有文献报道溶解方法的化合物，需通过前期实验来确定（建议先取少量样品进行尝试），包括产品的溶解情况、梯度设置、动物的耐受性等。

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请根据您的实验动物和给药方式选择适当的溶解配方/方案：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
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10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
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