EX229 is a benzimidazole derivative that functions as a potent allosteric agonist of AMP-activated protein kinase (AMPK)[1]. EX229 binds to AMPK with high specificity, exhibiting differential binding affinity for various isoforms: α1β1γ1 (Kd=0.06μM), α2β1γ1 (Kd=0.06μM), and α1β2γ1 (Kd=0.51μM)[2]. EX229 effectively regulates glucose transport and inhibits lipogenesis[3].
In vitro, treatment of C2C12 myotube cells with EX229 (2–25μM) for 12 hours significantly activated the AMPK signaling pathway, as indicated by a dose-dependent increase in AMPKα phosphorylation. This was accompanied by upregulation of key unfolded protein response (UPR) markers, including ATF4 and CHOP, at the protein level[4].
In vivo, daily intramuscular administration of EX229 (2.0mg/kg) for 8 weeks in a rat model of heart failure induced by coronary artery ligation significantly reversed the cardioprotective effects of Fuyu Decoction. This was demonstrated by a marked increase in left ventricular end-diastolic volume (LVEDV) and end-systolic volume (LVESV), along with a significant reduction in left ventricular ejection fraction (LVEF) and fractional shortening (LVFS)[5].
References:
[1] Lai YC, Kviklyte S, Vertommen D, et al. A small-molecule benzimidazole derivative that potently activates AMPK to increase glucose transport in skeletal muscle: comparison with effects of contraction and other AMPK activators. Biochem J. 2014 Jun 15;460(3):363-75.
[2] Xiao B, Sanders MJ, Carmena D, et al. Structural basis of AMPK regulation by small molecule activators. Nat Commun. 2013;4:3017.
[3] Bultot L, Jensen TE, Lai YC, et al. Benzimidazole derivative small-molecule 991 enhances AMPK activity and glucose uptake induced by AICAR or contraction in skeletal muscle. Am J Physiol Endocrinol Metab. 2016 Oct 1;311(4):E706-E719.
[4] Gong J, Wang L, Tao W, et al. AMPK Mediates Early Activation of the Unfolded Protein Response through a Positive Feedback Loop in Palmitate-Treated Muscle Cells. Front Biosci (Landmark Ed). 2023 Aug 7;28(8):159.
[5] Ma J, Xu Z, Zhu J, et al. Fuyu Decoction improves ventricular remodeling in rats with heart failure by inhibiting AMPK/mTOR pathway-mediated autophagy. Nan Fang Yi Ke Da Xue Xue Bao. 2023 Mar 20;43(3):466-473.
EX229是一种苯并咪唑衍生物，是一种有效的变构激动剂作用于AMP活化蛋白激酶（AMPK）[1]。EX229能够特异性地与AMPK结合，对α1β1γ1（Kd=0.06μM）、α2β1γ1（Kd=0.06μM）和α1β2γ1（Kd=0.51μM）不同亚型的亲和力存在差别[2]。EX229能有效调节葡萄糖转运和抑制脂肪生成[3]。
在体外，EX229（2-25μM）处理C2C12肌管细胞12小时，显著激活AMPK信号通路，表现为AMPKα磷酸化水平剂量依赖性升高，同时诱导未折叠蛋白反应（UPR）关键标志物ATF4和CHOP的蛋白表达上调[4]。
在体内，EX229（2.0mg/kg）每日肌肉注射处理冠状动脉结扎诱导的心力衰竭模型大鼠8周，能够显著逆转附萸汤对心力衰竭大鼠心功能指标的改善作用，表现为左心室舒张末期容积（LVEDV）和收缩末期容积（LVESV）显著增加，左心室射血分数（LVEF）和左室短轴缩短率（LVFS）显著降低[5]。