AM095 is a selective, orally bioavailable LPA1 antagonist with an IC50 value of 0.73μM for mouse LPA1[1]. AM095 can reduce the mRNA expression level of pro-inflammatory cytokines and inhibit the activation of NF-κB by antagonizing LPA1 activity[2]. AM095 has been widely used to inhibit the development of idiopathic pulmonary fibrosis and systemic fibrosis in different animal models[3].
In vitro, AM095 treatment (10μM) for 48h significantly inhibited Lysophosphatidic acid (LPA)-induced decrease in E-cadherin expression and reduced the expression levels of fibrosis factors (α-SMA and fibronectin)[4]. Pretreatment with 0.5µM AM095 for 3 hours significantly reversed Porphyromonas gingivalis-derived lipopolysaccharide (Pg-LPS)-induced decline in the viability of periodontal ligament stem cells (PDLSCs) and reduced the expression of IL-1β and TNF-α[5]. Pretreatment of MDA-MB-231 cells with 0.5µM AM095 for 5min significantly inhibited the proliferation of MDA-MB-231 cells induced by 30µM lysophosphatidylethanolamine (LPE) (24h)[6].
In vivo, AM095 treatment via oral administration at a dose of 30mg/kg/day for 8 weeks alleviated hyperglycemia and dyslipidemia and improved renal function in streptozotocin (STZ)-induced diabetic mice[7]. Gavage of AM095 at a dose of 10mg/kg once daily for 18 days reduced disease severity and increased the number of redifferentiated Schwann cells in a rat model of induced experimental autoimmune neuritis[8].
References:
[1] Swaney J S, Chapman C, Correa L D, et al. Pharmacokinetic and pharmacodynamic characterization of an oral lysophosphatidic acid type 1 receptor-selective antagonist[J]. The Journal of pharmacology and experimental therapeutics, 2011, 336(3): 693-700.
[2] Gaire B P, Sapkota A, Song M R, et al. Lysophosphatidic acid receptor 1 (LPA1) plays critical roles in microglial activation and brain damage after transient focal cerebral ischemia[J]. Journal of Neuroinflammation, 2019, 16(1): 170.
[3] Im D S. First-in-class antifibrotic therapy targeting type 1 lysophosphatidic acid receptor[J]. Archives of pharmacal research, 2012, 35(6): 945-948.
[4] Lee G H, Cheon J, Kim D, et al. Lysophosphatidic Acid Promotes Epithelial–Mesenchymal Transition in Kidney Epithelial Cells via the LPAR1/MAPK-AKT/KLF5 Signaling Pathway in Diabetic Nephropathy[J]. International Journal of Molecular Sciences, 2022, 23(18): 10497.
[5] Kim D H, Seo E J, Tigyi G J, et al. The role of lysophosphatidic acid receptor 1 in inflammatory response induced by lipopolysaccharide from Porphyromonas gingivalis in human periodontal ligament stem cells[J]. Intern J Oral Biol, 2020, 45: 42-50.
[6] Park S J, Lee K P, Im D S. Action and signaling of lysophosphatidylethanolamine in MDA-MB-231 breast cancer cells[J]. Biomolecules & Therapeutics, 2014, 22(2): 129.
[7] Lee J H, Sarker M K, Choi H, et al. Lysophosphatidic acid receptor 1 inhibitor, AM095, attenuates diabetic nephropathy in mice by downregulation of TLR4/NF-κB signaling and NADPH oxidase[J]. Biochimica et Biophysica Acta (BBA)-Molecular Basis of Disease, 2019, 1865(6): 1332-1340.
[8] Szepanowski F, Winkelhausen M, Steubing R D, et al. LPA1 signaling drives Schwann cell dedifferentiation in experimental autoimmune neuritis[J]. Journal of Neuroinflammation, 2021, 18(1): 293.
AM095是一种选择性、具有口服活性的LPA1受体拮抗剂，对小鼠LPA1的IC50值为0.73μM[1]。AM095通过拮抗LPA1活性，可降低促炎细胞因子的mRNA表达水平并抑制NF-κB活化[2]。AM095已广泛应用于多种动物模型中抑制特发性肺纤维化和系统性纤维化的进展[3]。
在体外，使用10μM的AM095处理48小时能显著抑制Lysophosphatidic acid (LPA)诱导的E-钙黏蛋白表达下降，并降低纤维化因子（α-SMA和纤连蛋白）的表达水平[4]。用0.5μM的AM095预处理人牙周膜干细胞(PDLSCs)3小时，可显著逆转牙龈卟啉单胞菌脂多糖(Pg-LPS)诱导的细胞活力下降，并减少IL-1β和TNF-α的表达[5]。以0.5μM的AM095预处理MDA-MB-231细胞5分钟，能显著抑制30µM的lysophosphatidylethanolamine (LPE)处理24小时诱导的细胞增殖[6]。
在体内，每日口服30mg/kg/day剂量的AM095连续8周，可缓解链脲佐菌素(STZ)诱导的糖尿病小鼠的高血糖和血脂异常，并改善肾功能[7]。在实验性自身免疫性神经炎大鼠模型中，每日灌胃10mg/kg 剂量的AM095连续18天，能减轻疾病严重程度并增加去分化雪旺细胞的数目[8]。