PARP (IC50 =120 μM)

200 μM 时，BGP-15 可抑制甲磺酸伊马替尼引起的氧化损伤，停止高能磷酸盐的消耗，并通过抑制 p38 MAP 损伤、JNK 激活以及传感 Akt 和 GSK-3beta 来修改甲磺酸伊马替尼的信号传导作用。 5]。

在老年 mdx 小鼠中，BGP-15（15 mg/kg，颈部）对骨骼肌病理学没有影响 [1]。虽然没有阻止膈肌萎缩，但 10 天的 BGP-15 治疗显着增加了支架模型中的膈肌纤维功能（约 100%）。此外，通过防止与 PARP-1 抑制和 HSP72 激活相关的肌球蛋白 PTM，该疗法可增强隔膜内容和功能 [2]。在 Ntg 小鼠或正常野生型小鼠的独立队列中，使用形态学、心脏功能和心电图测量来评估 BGP-15（每天 15 mg/kg，盐水中）的效果。 BGP-15 治疗降低了肺重量和心房大小的增长。使用 BGP-15 药物可以预防心律失常或减轻其后果。在 HF+AF 范例中，BGP-15 处理与 PR 间隔相关联 [3]。在枕头喂养的兔子中，BGP-15（10 和 30 mg/kg）分别使玉米粥的含量提高了 50% 和 70%，但在正常兔子中则不然。经过 5 天的 BGP-15 治疗后，遗传性胰岛素抵抗 GK 的突变输注率以剂量依赖性方式增加。与二氧化碳相比，最有效的剂量是 20 mg/kg，这会增加 71% 的胰岛素负荷 [4]。

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[6]。

在这项研究中，研究人员研究了著名的细胞抑制剂甲磺酸伊马替尼(格列卫)的心脏毒性作用，并提供了一种新型胰岛素增敏剂bp -15的心脏保护作用的证据。在Langendorff大鼠心脏灌注系统中评价甲磺酸伊马替尼的心脏毒性作用。采用(31)P NMR原位监测心肌高能磷酸水平(磷酸肌酸(PCr)和ATP)。蛋白氧化，脂质过氧化和信号通路的激活从冷冻夹住的心脏。甲磺酸伊马替尼(20mg /kg)长期治疗心脏导致心脏毒性，其特征是高能磷酸盐(PCr和ATP)耗损，蛋白质氧化和脂质过氧化显著增加。甲磺酸伊马替尼治疗诱导MAP激酶(包括ERK1/2、p38和JNK)的激活以及Akt和gsk -3 β的磷酸化。BGP-15 (200 μM)可抑制甲磺酸伊马替尼诱导的氧化损伤，减轻高能磷酸盐的消耗，通过抑制p38 MAP激酶和JNK活化改变甲磺酸伊马替尼的信号传导作用，诱导Akt和gsk -3 β磷酸化。bp -15对p38和JNK活化的抑制作用可能是显著的，因为这些激酶有助于离体灌注心脏的细胞死亡和炎症。[5]

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

350.128

C, 47.87; H, 6.89; Cl, 20.19; N, 15.95; O, 9.11

66611-37-8

66611-38-9; 66611-37-8 (HCl)

9884807

White solid powder

2.807

81.47

4

5

6

22

306

0

Cl[H].Cl[H].O([H])C([H])(C([H])([H])O/N=C(/C1=C([H])N=C([H])C([H])=C1[H])\N([H])[H])C([H])([H])N1C([H])([H])C([H])([H])C([H])([H])C([H])([H])C1([H])[H]

ISGGVCWFTPTHIX-UHFFFAOYSA-N

InChI=1S/C14H22N4O2.2ClH/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);2*1H

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

BGP15 hydrochloride; BGP15 HCl; BGP15; N-(2-Hydroxy-3-(piperidin-1-yl)propoxy)nicotinimidamide dihydrochloride; 3-Pyridinecarboximidamide, N-(2-hydroxy-3-(1-piperidinyl)propoxy)-, hydrochloride (1:2); RLN2GTG4YS; N'-(2-hydroxy-3-piperidin-1-ylpropoxy)pyridine-3-carboximidamide;dihydrochloride; 3-Pyridinecarboximidamide, N-(2-hydroxy-3-(1-piperidinyl)propoxy)-, dihydrochloride; BGP 15; BGP-15

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)

H2O : ~100 mg/mL (~284.68 mM)
DMSO : ~11.33 mg/mL (~32.25 mM)

配方 1 中的溶解度: ≥ 2.5 mg/mL (7.12 mM) (饱和度未知) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将100 μL 25.0 mg/mL澄清DMSO储备液加入到400 μL PEG300中，混匀；然后向上述溶液中加入50 μL Tween-80，混匀；加入450 μL生理盐水定容至1 mL。
*生理盐水的制备：将 0.9 g 氯化钠溶解在 100 mL ddH₂O中，得到澄清溶液。

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配方 2 中的溶解度: ≥ 2.5 mg/mL (7.12 mM) (饱和度未知) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 25.0 mg/mL澄清DMSO储备液加入900 μL 20% SBE-β-CD生理盐水溶液中，混匀。
*20% SBE-β-CD 生理盐水溶液的制备（4°C，1 周）：将 2 g SBE-β-CD 溶解于 10 mL 生理盐水中，得到澄清溶液。

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配方 3 中的溶解度: ≥ 2.5 mg/mL (7.12 mM) (饱和度未知) in 10% DMSO + 90% Corn Oil (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 25.0 mg/mL 澄清 DMSO 储备液加入到 900 μL 玉米油中并混合均匀。

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配方 4 中的溶解度: 100 mg/mL (284.68 mM) in PBS (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液; 超声助溶.

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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));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
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；
3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例;
4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶;
5、为保证最佳实验结果，工作液请现配现用！
6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们;
7、 以上所有助溶剂都可在 Invivochem.cn网站购买。