Ingliforib (CP 368296)
(Synonyms: CP 368296; GPi 296) 目录号 : GC32658
Ingliforib (CP 368296) is a glycogen phosphorylase (GP) inhibitor, with IC50s of 52, 352 and 150 nM for liver, muscle and brain glycogen phosphorylase, and has cardioprotective activity.
Cas No.:186392-65-4
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >99.50%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
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Animal experiment: |
Rabbits[1]Male New Zealand White rabbits (3 to 4 kg) are used in the assay. At least 1 h after surgery, when arterial pressure, heart rate (HR), and rate-pressure product (RPP) have stabilized for at least 30 min (baseline), the rabbits receive a bolus of either 15.4 mg/kg of Ingliforib or vehicle (administered in 15 s), followed by a constant infusion of 23.1 mg/kg/h Ingliforib or vehicle at the same dose volume for a total of 3.5 h. |
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References: [1]. Tracey WR, et al. Cardioprotective effects of ingliforib, a novel glycogen phosphorylase inhibitor. Am J Physiol Heart Circ Physiol. 2004 Mar;286(3):H1177-84. |
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Ingliforib (CP 368296) is a glycogen phosphorylase (GP) inhibitor, with IC50s of 52, 352 and 150 nM for liver, muscle and brain glycogen phosphorylase, and has cardioprotective activity.
[1] Tracey WR, et al. Am J Physiol Heart Circ Physiol. 2004 Mar;286(3):H1177-84.
| Cas No. | 186392-65-4 | SDF | |
| 别名 | CP 368296; GPi 296 | ||
| Canonical SMILES | O=C(C(N1)=CC2=C1C=CC(Cl)=C2)N[C@@H](CC3=CC=CC=C3)[C@@H](O)C(N4C[C@@H](O)[C@@H](O)C4)=O | ||
| 分子式 | C23H24ClN3O5 | 分子量 | 457.91 |
| 溶解度 | DMSO : 130 mg/mL (283.90 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 | 2.1838 mL | 10.9192 mL | 21.8384 mL |
| 5 mM | 0.4368 mL | 2.1838 mL | 4.3677 mL |
| 10 mM | 0.2184 mL | 1.0919 mL | 2.1838 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。
Cardioprotective effects of Ingliforib, a novel glycogen phosphorylase inhibitor
Am J Physiol Heart Circ Physiol 2004 Mar;286(3):H1177-84.PMID:14615278DOI:10.1152/ajpheart.00652.2003.
Interventions such as glycogen depletion, which limit myocardial anaerobic glycolysis and the associated proton production, can reduce myocardial ischemic injury; thus it follows that inhibition of glycogenolysis should also be cardioprotective. Therefore, we examined whether the novel glycogen phosphorylase inhibitor 5-Chloro-N-[(1S,2R)-3-[(3R,4S)-3,4-dihydroxy-1-pyrrolidinyl)]-2-hydroxy-3-oxo-1-(phenylmethyl)propyl]-1H-indole-2-carboxamide (Ingliforib; CP-368,296) could reduce infarct size in both in vitro and in vivo rabbit models of ischemia-reperfusion injury (30 min of regional ischemia, followed by 120 min of reperfusion). In Langendorff-perfused hearts, constant perfusion of Ingliforib started 30 min before regional ischemia and elicited a concentration-dependent reduction in infarct size; infarct size was reduced by 69% with 10 microM Ingliforib. No significant drug-induced changes were observed in either cardiac function (heart rate, left ventricular developed pressure) or coronary flow. In open-chest anesthetized rabbits, a dose of Ingliforib (15 mg/kg loading dose; 23 mg.kg(-1).h(-1) infusion) selected to achieve a free plasma concentration equivalent to an estimated EC(50) in the isolated hearts (1.2 microM, 0.55 microg/ml) significantly reduced infarct size by 52%, and reduced plasma glucose and lactate concentrations. Furthermore, myocardial glycogen phosphorylase a and total glycogen phosphorylase activity were reduced by 65% and 40%, respectively, and glycogen stores were preserved in ingliforib-treated hearts. No significant change was observed in mean arterial pressure or rate-pressure product in the Ingliforib group, although heart rate was modestly decreased postischemia. In conclusion, glycogen phosphorylase inhibition with Ingliforib markedly reduces myocardial ischemic injury in vitro and in vivo; this may represent a viable approach for both achieving clinical cardioprotection and treating diabetic patients at increased risk of cardiovascular disease.
Discovery of novel heterocyclic derivatives as potential glycogen phosphorylase inhibitors with a cardioprotective effect
Bioorg Chem 2022 Dec;129:106120.PMID:36108587DOI:10.1016/j.bioorg.2022.106120.
The purpose of this study was to evaluate the effect of GP inhibitor as a potential pharmaceutical target on MI/R injury. Four different structural types of novel compounds (I, II, III, and IV) were designed and synthesized, obtaining 31 novel GP inhibitors. SAR studies revealed that the conjugates of 5-chloroindole with benzo six-membered heterocyclic were found to elevate the activity. In particular, compound IIIh (IC50 = 0.21 ± 0.03 µM) emerged as a potent derivative against RMGPa, being approximately 2-fold less potent than that of PSN-357. In order to screen out a compound for in vivo activity test, we further conducted an experiment of inhibition against three different subtypes of GPa (HLGPa, HMGPa and HBGPa) and the corresponding affinity experiment. As a result, compound IIIh showed strong inhibitory activity against the above three subtypes of GP, especially on HBGPa (IC50 = 0.09 ± 0.002 µM), which was relatively close to that of positive control Ingliforib (IC50 = 0.16 ± 0.02 µM). The affinity of compound IIIh to HBGPa was 4.3 times higher than that of HLGPa, and 1.1 times higher than that of HMGPa. This fact further proved that compound IIIh has a higher inhibitory effect on HMGPa than the other two subtypes. Besides, in vivo activity evaluation demonstrated that compound IIIh exhibited obviously cardioprotective effect on MI/R injury mice. The discovery of compound IIIh provides a new strategy for developing novel GP inhibitors with myocardial ischemia protection.
Development and evaluation of novel solid nanodispersion system for oral delivery of poorly water-soluble drugs
J Control Release 2013 Jul 10;169(1-2):150-61.PMID:23570985DOI:10.1016/j.jconrel.2013.03.032.
The aim of the present study was to develop and evaluate a novel drug solubilization platform (so-called solid nanodispersion) prepared by a simple co-grinding and solvent-free process. Using structurally diverse model compounds from the Pfizer drug library, including Ingliforib, furosemide and celecoxib, we successfully prepared stable solid nanodispersions (SNDs) without the use of solvent or heat. Stable colloidal particles (<350 nm) containing drug, polyvinylpyrrolidone (PVP) K12 and sodium dodecyl sulfate (SDS) in 1:2.75:0.25 ratio were produced after 2 h of co-grinding. The composition and particle size of SNDs were optimized by varying the grinding media size, powder-to-grinding media ratio, milling speed and milling time. The resulting formulations contained crystalline drug and were stable at room temperature for over one month. Greater than 80% of the drug was released from the SND in less than 30 min, with sustained supersaturation over 4 h. Using furosemide (BCS class IV compound) as a model compound, we conducted transport studies with Madin-Darby canine kidney cells transfected with human MDR1 gene (MDCK/MDR1), followed by pharmacokinetics studies in rats. Results showed that the SND formulation enhanced the absorptive flux of furosemide by more than 3-fold. In the pharmacokinetics studies, the SND formulation increased C(max) and AUC of furosemide by 36.6 and 43.2 fold respectively, relative to Methocel formulation. Interestingly, physical mixture containing furosemide, PVP K12 and SDS produced a similar level of oral exposure as the SNDs, albeit with a longer T(max) than the SND formulation. The results suggest that PVP K12 and SDS were able to increase the furosemide free fraction available for oral absorption. Low solubility, poor permeability, and high first-pass effect of furosemide may also have produced the effect that small improvements in solubilization resulted in significant potentiation of the oral exposure of the physical mixture. However the use of a physical mixture of drug, polymer and surfactant, to increase drug bioavailability cannot be generalized to all drugs. There are only a few reported cases of such phenomenon. While SNDs may not be the only option to solubilize compounds in every case, SNDs are expected to be applicable to a broader chemical space of pharmaceutical compounds compared to a physical mixture. Ultimately, the formulation scientist will have to exercise judgment in choosing the appropriate formulation strategy for the compound of interest. SNDs represent a significant improvement over current enabling technologies such as nanocrystal and spray-dried dispersion technologies, in that SNDs are simple, do not require solvent or heat, are applicable to a structurally diverse chemical space, and are readily amenable to the development of solid dosage forms.