A922500 is a potent, selective, and orally bioavailable diacylglycerol acyltransferase 1 (DGAT-1) inhibitor with IC50 values of 9 and 22nM against human and mouse DGAT-1, respectively[1]. DGAT-1 is the key rate-limiting enzyme that catalyzes the final step of triglyceride synthesis by transferring fatty acyl groups to diacylglycerol to form triglycerides[2]. A922500 is usualy used in studies of type 2 diabetes, obesity, and lipid-metabolism disorders[3].
In vitro, A922500（10 or 50μM; 54 hpi to Day 8）reduces cytoplasmic lipid droplet area, increases mitochondrial activity and total cell number, and improves post-vitrification survival in bovine IVP blastocysts without affecting blastocyst yield[4].A922500 (40μM; 24h) reduced neutral lipid droplet formation and significantly decreased cell viability in HuH7 hepatocytes under non-toxic oleic acid loading[5].
In vivo, A922500 (30mg/kg/day; 6 weeks; p.o.) reduced triglyceride content in bronchoalveolar lavage macrophages but did not decrease lung bacillary burden or inflammation in Mycobacterium tuberculosis-infected C3HeB/FeJ mice[6]. A922500 (3mg/kg; p.o.) reversed sepsis-induced hepatic lipid droplet accumulation, reduced AST/ALT levels, and suppressed lipid peroxidation markers 4-HNE and 3-NT in caecal ligation and puncture (CLP) mouse model[7].
References:
[1] King AJ, Segreti JA, Larson KJ, et al. Diacylglycerol acyltransferase 1 inhibition lowers serum triglycerides in the Zucker fatty rat and the hyperlipidemic hamster. J Pharmacol Exp Ther. 2009;330(2):526-531.
[2] Lee K, Goo JI, Jung HY, et al. Discovery of a novel series of benzimidazole derivatives as diacylglycerol acyltransferase inhibitors. Bioorg Med Chem Lett. 2012;22(24):7456-7460.
[3] Tsuda N, Kumadaki S, Higashi C, et al. Intestine-targeted DGAT1 inhibition improves obesity and insulin resistance without skin aberrations in mice. PLoS One. 2014;9(11):e112027.
[4] Cañón-Beltrán K, Giraldo-Giraldo J, Cajas YN, et al. Inhibiting diacylglycerol acyltransferase-1 reduces lipid biosynthesis in bovine blastocysts produced in vitro. Theriogenology. 2020;158:267-276.
[5] Moliterni C, Vari F, Schifano E, et al. Lipotoxicity of palmitic acid is associated with DGAT1 downregulation and abolished by PPARα activation in liver cells. J Lipid Res. 2024;65(12):100692.
[6] Ruelas Castillo J, Guerrini V, Quijada D, et al. Pharmacologic Inhibition of Macrophage Triglyceride Biosynthesis Pathways Does Not Improve Mycobacterium tuberculosis Control in Infected Mice. J Infect Dis. 2025;231(5):1141-1149.
[7] Teixeira L, Pereira-Dutra FS, Reis PA, et al. Prevention of lipid droplet accumulation by DGAT1 inhibition ameliorates sepsis-induced liver injury and inflammation. JHEP Rep. 2023;6(2):100984.
A922500是一种有效、选择性高且具有口服活性的二酰基甘油酰基转移酶1（DGAT-1）抑制剂，对人源和小鼠DGAT-1的IC50值分别为9和22nM[1]。DGAT-1是催化甘油三酯合成最后一步的关键限速酶，通过将脂肪酰基转移到二酰基甘油上形成甘油三酯[2]。A922500常用于2型糖尿病、肥胖症和脂代谢紊乱等研究[3]。
在体外，A922500（10或50μM；受精后54h至第8天）可减少牛体外受精囊胚的细胞质脂滴面积，增强线粒体活性和总细胞数，并提高玻璃化冷冻后的存活率，且不影响囊胚形成率[4]。A922500（40μM；24h）在非毒性油酸负荷下可减少HuH7肝细胞的中性脂滴形成，并显著降低细胞活力[5]。
在体内，A922500（30mg/kg/天；6周；口服）可降低结核分枝杆菌感染的C3HeB/FeJ小鼠的支气管肺泡灌洗巨噬细胞中的甘油三酯含量，但未能减少肺部细菌负荷或炎症[6]。A922500（3mg/kg；口服）在盲肠结扎穿孔（CLP）小鼠模型中可逆转脓毒症诱导的肝脏脂滴积聚，降低AST/ALT水平，并抑制脂质过氧化标志物4-HNE和3-NT[7]。