BMS 309403
(Synonyms: Adipocyte FABP Inhibitor, AFABP Inhibitor, ALBP Inhibitor, aP2 Inhibitor, FABP4 Inhibitor, Fatty Acid Binding Protein 4 Inhibitor) 目录号 : GC11894
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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。
Cas No.:300657-03-8
Sample solution is provided at 25 µL, 10mM.
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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]。
| Cell experiment [1]: | |
Cell lines | A2780 cells |
Preparation Method | The A2780 cells were cultured in a medium containing 10% fetal bovine serum (FBS), 100IU/ml penicillin-streptomycin and 2mM glutamine, with the culture conditions set at 37°C, 5% CO2 and 95% humidity. A2780 cells were seeded at a density of 2.35×104 cells/ml in 96-well plates and cultured in a medium containing 5% FBS overnight. Then, different concentrations of BMS 309403 (0, 20, 40, 60, 80, and 100μM) were added and the cells were treated for 72 hours. Finally, the number of viable cells was determined. |
Reaction Conditions | 0, 20, 40, 60, 80, and 100μM; 72h |
Applications | BMS 309403 treatment reduced cell viability of A2780 cells in a dose-dependent manner. |
| Animal experiment [2]: | |
Animal models | Male C57BL/6J mice |
Preparation Method | Male C57BL/6J mice (9-10 weeks old, weighing 25-27g) were housed in an environment with a temperature controlled at 23±2°C and a 12-hour light/12-hour dark cycle. Mice had free access to food and water. After an adaptation period of 1 week, the mice were randomly divided into 4 groups (n ≥ 6 in each group): control group, hyperuricemic nephropathy (HN) group, allopurinol group, and FABP4i group. The HN mouse model was established by intragastric administration. A 200μl solution of adenine (160mg/kg/day) and potassium oxonate (2400mg/kg/day) dissolved in double-distilled water was administered intragastrically daily for 3 weeks. The control group was given the same volume of double-distilled water. 3 hours after intragastric administration, the mice were given allopurinol (10mg/kg/day) or BMS 309403 (40mg/kg/day) daily. After 3 weeks, the mice were sacrificed and kidney samples were collected for subsequent analysis. |
Dosage form | 40mg/kg/day for 3 weeks; p.o. |
Applications | BMS 309403 treatment suppressed kidney inflammation and fibrosis in hyperuricemic mice. |
References: | |
| Cas No. | 300657-03-8 | SDF | |
| 别名 | Adipocyte FABP Inhibitor, AFABP Inhibitor, ALBP Inhibitor, aP2 Inhibitor, FABP4 Inhibitor, Fatty Acid Binding Protein 4 Inhibitor | ||
| 化学名 | 2-((2'-(5-ethyl-3,4-diphenyl-1H-pyrazol-1-yl)-[1,1'-biphenyl]-3-yl)oxy)acetic acid | ||
| Canonical SMILES | OC(COC1=CC(C2=CC=CC=C2N3N=C(C4=CC=CC=C4)C(C5=CC=CC=C5)=C3CC)=CC=C1)=O | ||
| 分子式 | C31H26N2O3 | 分子量 | 474.55 |
| 溶解度 | ≥ 18.15mg/mL in DMSO | 储存条件 | Store at -20°C |
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1 mg | 5 mg | 10 mg |
| 1 mM | 2.1073 mL | 10.5363 mL | 21.0726 mL |
| 5 mM | 421.5 μL | 2.1073 mL | 4.2145 mL |
| 10 mM | 210.7 μL | 1.0536 mL | 2.1073 mL |
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- Purity: >98.00% Appearance: A solid
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