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]。