PF-06882961
目录号 : GC38832
PF-06882961是一种强效、具有口服活性的胰高血糖素样肽-1受体（GLP-1R）激动剂
Cas No.:2230198-02-2
Sample solution is provided at 25 µL, 10mM.
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PF-06882961 is a potent, orally active glucagon-like peptide-1 receptor (GLP-1R) agonist[1]. GLP-1R, a class B G-protein-coupled receptor mainly expressed in pancreatic β-cells and the central nervous system, binds GLP-1 to enhance glucose-dependent insulin secretion, suppress appetite, and delay gastric emptying[2]. PF-06882961 is usually used in the research of metabolic diseases such as type 2 diabetes[3][4].
In vitro, treatment of phenylephrine (PE)-induced neonatal rat cardiomyocytes (NRCMs) with PF-06882961(0-1.2μg/mL; 24h) significantly enhanced cardiomyocyte viability, attenuated PE-induced hypertrophy, reduced cell surface area, and decreased expression of hypertrophic markers (ANP, BNP, and β-MHC) without cytotoxicity[5]. Treatment of monkey Flpin-HEK293 cells with PF-06882961(0.37-30μM; 10min) showed moderate potency with an IC50 value of 6.9μM in the hERG potassium ion channel assay[6].
In vivo, PF-06882961 (1mg/kg/day; p.o.; 8 weeks) significantly improved cardiac function, attenuated cardiac hypertrophy and fibrosis, reduced heart weight to body weight (HW/BW), heart weight to tibia length (HW/TL), cardiomyocyte cross-sectional area (CSA) and collagen deposition, increased phosphorylated AMPKα and HSP70, decreased pro-apoptotic proteins (Bax and cleaved caspase-3), and enhanced autophagy marker Atg5 and anti-apoptotic Bcl-2 in a mouse model of aortic banding (AB)[5]. PF-06882961 (2mg/kg; single oral administration; OGTT performed 1 hour post-dose) significantly reduced blood glucose levels in hGLP-1R knock-in mice during the oral glucose tolerance test[7].
References:
[1] Griffith DA, Edmonds DJ, Fortin JP, et al. A Small-Molecule Oral Agonist of the Human Glucagon-like Peptide-1 Receptor. J Med Chem. 2022;65(12):8208-8226.
[2] Zheng Z, Zong Y, Ma Y, et al. Glucagon-like peptide-1 receptor: mechanisms and advances in therapy. Signal Transduct Target Ther. 2024;9(1):234.
[3] Saxena AR, Gorman DN, Esquejo RM, et al. Danuglipron (PF-06882961) in type 2 diabetes: a randomized, placebo-controlled, multiple ascending-dose phase 1 trial. Nat Med. 2021;27(6):1079-1087.
[4] Karakasis P, Patoulias D, Pamporis K, et al. Safety and efficacy of the new, oral, small-molecule, GLP-1 receptor agonists orforglipron and danuglipron for the treatment of type 2 diabetes and obesity: systematic review and meta-analysis of randomized controlled trials. Metabolism. 2023;149:155710.
[5] Wang P, Guo Z, Kong CY, et al. Danuglipron Ameliorates Pressure Overload-Induced Cardiac Remodelling Through the AMPK Pathway. J Cell Mol Med. 2025;29(5):e70488.
[6] Sun J, Xiao Y, Hu X, et al. Toxicology profile of a novel GLP-1 receptor biased agonist-SAL0112 in nonhuman primates. Toxicol Appl Pharmacol. 2024;492:117125.
[7] Chen X, Xu S, Yang S, et al. Discovery of Selenium-Containing Derivatives as Potent and Orally Bioavailable GLP-1R Agonists. J Med Chem. 2025;68(3):3386-3408.
PF-06882961是一种强效、具有口服活性的胰高血糖素样肽-1受体（GLP-1R）激动剂[1]。GLP-1R是一种主要表达于胰岛β细胞和中枢神经系统的B类G蛋白偶联受体，其与GLP-1结合后可增强葡萄糖依赖性的胰岛素分泌、抑制食欲并延缓胃排空[2]。PF-06882961常用于代谢性疾病（如2型糖尿病）的研究[3][4]。
在体外实验中，使用PF-06882961（0.1μg/mL；24小时）处理苯肾上腺素（PE）诱导的新生大鼠心肌细胞（NRCMs），可显著提高心肌细胞存活率，减轻PE诱导的心肌肥厚，减小细胞表面积，并降低肥厚标志物（ANP、BNP和β-MHC）的表达，且无明显细胞毒性[5]。在猴源Flpin-HEK293细胞中，PF-06882961（0.37–30μM；10分钟）在hERG钾离子通道实验中表现出中等活性，其 IC50值为 6.9μM[6]。
在体内实验中，PF-06882961（1mg/kg/天；口服；持续8周）可显著改善主动脉缩窄（AB）小鼠模型的心脏功能，减轻心肌肥厚和纤维化，降低心脏重量/体重比（HW/BW）、心脏重量/胫骨长度比（HW/TL）、心肌细胞横截面积（CSA）及胶原沉积，增加AMPKα磷酸化和HSP70 表达，降低促凋亡蛋白（Bax、活性 caspase-3）水平，增强自噬标志物（Atg5）和抗凋亡蛋白（Bcl-2）表达[5]。PF-06882961（2mg/kg；单次口服给药；给药1小时后进行口服葡萄糖耐量试验）在hGLP-1R敲入小鼠中显著降低了口服葡萄糖耐量试验中的血糖水平[7]。
| Cell experiment [1]: | |
Cell lines | neonatal rat cardiomyocytes (NRCMs) |
Preparation Method | 75% alcohol sterilises the suckling Sprague–Dawley rat that has just been born for 1–2 days and quickly removes its heart, which was rinsed and minced into small pieces. Digest the ventricular myocardium of the neonatal rat hearts using 0.125% trypsin solution prepared with D-Hanks solution for 15min. This digestion process was repeated four times, after which 16mL of Dulbecco's modified Eagle's medium/nutrient mixture F12 containing 4mL of fetal bovine serum was added to terminate the digestion. The neonatal rat cardiomyocytes (NRCMs) were isolated using differential adhesion techniques and cultured in DMEM/F12 medium containing 15% FBS, 5-bromodeoxyuridine (0.1mM), and penicillin/streptomycin for 48h. Next, the cytotoxicity of PF-06882961 on cardiomyocytes was assessed. Cells were treated for 24h with various concentrations of PF-06882961 (0, 0.05, 0.1, 0.3, 0.9, 1.2μg/mL) or an equal volume of vehicle. Cell viability was then determined using the enhanced cell counting kit according to the manufacturer's protocol. Absorbance was measured at 450nm using a Synergy HT Multi-Detection Microplate Reader. |
Reaction Conditions | 0-1.2μg/mL; 24h |
Applications | Treatment of phenylephrine (PE)-induced neonatal rat cardiomyocytes (NRCMs) with PF-06882961 significantly enhanced cardiomyocyte viability. |
| Animal experiment [1]: | |
Animal models | C57BL/6 mice |
Preparation Method | Adult male wild-type C57BL/6 mice (8–10weeks old, body weight: 23.5–27.5g) were acclimated in laboratory environment for 1 week. Then, pressure overload (PO)-induced cardiac hypertrophy model in C57BL/6 mice was established using aortic banding (AB) surgery. Then AMPKα2 knockout mice (AMPKα2−/−) were generated and bred. In the next experimental stage, we randomly assigned the experimental mice to four groups: WT (n=10), sham-AMPKα2−/− + PF-06882961 (n=10), AB-AMPKα2−/− + vehicle (n=10), and AB-AMPKα2−/− + PF-06882961 (n=10) with intragastric administration of PF-06882961 (1mg/kg/day) or saline for 8 weeks, which was initiated 3 days after AB surgery. After 8 weeks of feeding, the surviving mice were randomly selected for echocardiography to assess their cardiac function. Then the body weight, heart weight, lung weight, and tibial length of each mouse were measured and recorded after euthanized by administering excessive sodium pentobarbital (200mg/kg, i.p.). Hearts tissue were collected for further analyses. |
Dosage form | 1mg/kg/day; p.o.; 8 weeks |
Applications | PF-06882961 significantly improved cardiac function, attenuated cardiac hypertrophy and fibrosis, reduced heart weight to body weight (HW/BW), heart weight to tibia length (HW/TL), cardiomyocyte cross-sectional area (CSA) and collagen deposition. |
References: | |
| Cas No. | 2230198-02-2 | SDF | |
| Canonical SMILES | OC(C1=CC=C(N=C(CN2CCC(C3=NC(OCC4=CC=C(C#N)C=C4F)=CC=C3)CC2)N5C[C@H]6OCC6)C5=C1)=O | ||
| 分子式 | C31H30FN5O4 | 分子量 | 555.6 |
| 溶解度 | DMSO: 125 mg/mL (224.98 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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1 mg | 5 mg | 10 mg |
| 1 mM | 1.7999 mL | 8.9993 mL | 17.9986 mL |
| 5 mM | 360 μL | 1.7999 mL | 3.5997 mL |
| 10 mM | 180 μL | 899.9 μL | 1.7999 mL |
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