BMS 309403 is a potent, orally active and selective inhibitor of adipocyte fatty acid binding protein (FABP4), with an IC50 value of 0.71μM [1]. The pyrazole core and the 4-position aromatic ring of BMS 309403 can respectively be inserted into two different hydrophobic pockets of the lipid transporter domain of FABP4 to exhibit inhibitory effect and reduce lipid accumulation[2]. BMS 309403 has been widely used to attenuate a systemic inflammatory damage in mice [3].
In vitro, BMS 309403 treatment for 72 hours significantly inhibited the proliferation of A2780 cells, SKOV3 cells and OVCAR3 cells, with IC50 values of 48.1µM, 71.2µM and 60.5µM, respectively[4]. 5μM dose of BMS 309403 pretreatment for 2 hours significantly inhibited the DNA synthesis and cell migration of rat vascular smooth muscle cells (VSMCs) induced by PDGF-BB (10ng/ml; 24 hours)[5]. Treatment with 50µM BMS 309403 for 24 hours can alleviate endoplasmic reticulum stress in H9c2 cardiomyocytes under hypoxic conditions and reduce cell apoptosis[6].
In vivo, BMS 309403 treatment via oral administration at a dose of 40mg/kg/day for 6 consecutive weeks could lead to a reduction in liver fat infiltration in ob/ob mice, a significant decrease in total liver triglyceride content, and alleviation of atherosclerosis[7]. For three consecutive weeks, intragastric administration of 40mg/kg/day dose of BMS 309403 significantly inhibited renal inflammation and fibrosis in mice with hyperuricemia, improved renal dysfunction, suppressed the mRNA levels of KIM-1 and NGAL, and reduced the expression of pro-inflammatory cytokines and fibrotic proteins in the damaged kidneys[8].
References:
[1] Okada T, Hiromura M, Otsuka M, et al. Synthesis of BMS-309403-related compounds, including [14C] BMS-309403, a radioligand for adipocyte fatty acid binding protein[J]. Chemical and Pharmaceutical Bulletin, 2012, 60(1): 164-168.
[2] Chen S, Pan Z, Liu M, et al. Recent Advances on Small-Molecule Inhibitors of Lipocalin-like Proteins[J]. Journal of Medicinal Chemistry, 2024, 67(7): 5144-5167.
[3] Su H, Zou Y, Chen G, et al. Exploration of fragment binding poses leading to efficient discovery of highly potent and orally effective inhibitors of FABP4 for anti-inflammation[J]. Journal of Medicinal Chemistry, 2020, 63(8): 4090-4106.
[4] Lemberger L, Wagner R, Heller G, et al. Pharmacological inhibition of lipid import and transport proteins in ovarian cancer[J]. Cancers, 2022, 14(23): 6004.
[5] Okamura Y, Otani K, Sekiguchi A, et al. Vasculo-protective effect of BMS-309403 is independent of its specific inhibition of fatty acid-binding protein 4[J]. Pflügers Archiv-European Journal of Physiology, 2017, 469(9): 1177-1188.
[6] Sun F, Du J, Li H, et al. FABP4 inhibitor BMS309403 protects against hypoxia‐induced H9c2 cardiomyocyte apoptosis through attenuating endoplasmic reticulum stress[J]. Journal of Cellular and Molecular Medicine, 2020, 24(19): 11188-11197.
[7] Furuhashi M, Tuncman G, Görgün C Z, et al. Treatment of diabetes and atherosclerosis by inhibiting fatty-acid-binding protein aP2[J]. Nature, 2007, 447(7147): 959-965.
[8] Shi M, Guo F, Liao D, et al. Pharmacological inhibition of fatty acid-binding protein 4 alleviated kidney inflammation and fibrosis in hyperuricemic nephropathy[J]. European journal of pharmacology, 2020, 887: 173570.
BMS 309403是一种强效、具有口服活性且选择性的adipocyte fatty acid binding protein (FABP4)抑制剂，IC50值为0.71μM[1]。BMS 309403的吡唑核心和4位芳环可分别插入FABP4脂质转运结构域的两个不同疏水口袋，从而发挥抑制作用并减少脂质积累[2]。BMS 309403已广泛用于减轻小鼠的全身性炎症损伤[3]。
在体外，BMS 309403处理72小时显著抑制了A2780细胞、SKOV3细胞和OVCAR3细胞的增殖，IC50值分别为48.1µM、71.2µM和60.5µM[4]。用5μM的BMS 309403预处理2小时显著抑制了PDGF-BB诱导的大鼠血管平滑肌细胞(VSMCs)的DNA合成和细胞迁移[5]。用50µM的BMS 309403处理24小时可减轻低氧条件下H9c2心肌细胞的内质网应激并减少细胞凋亡[6]。
在体内，连续6周每日口服40mg/kg剂量的BMS 309403可导致ob/ob小鼠肝脏脂肪浸润减少，总肝甘油三酯含量显著下降，并减轻动脉粥样硬化[7]。连续三周每日灌胃给予40mg/kg/day剂量的BMS 309403显著抑制了高尿酸血症小鼠的肾脏炎症和纤维化，改善了肾功能障碍，抑制了KIM-1和NGAL的mRNA水平，并降低了受损肾脏中促炎细胞因子和纤维化蛋白的表达[8]。