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Chemical Structure| 300657-03-8 Chemical Structure| 300657-03-8

Structure of BMS-309403
CAS No.: 300657-03-8

Chemical Structure| 300657-03-8

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BMS-309403 is a potent, orally active, and selective inhibitor of adipocyte fatty acid binding protein (FABP4, aP2) with Kis of <2, 250, and 350 nM for FABP4, FABP3, and FABP5, respectively. It interacts with the fatty-acid-binding pocket within the protein's interior and competitively inhibits endogenous fatty acids binding. BMS-309403 improves endothelial function in apolipoprotein E-deficient mice and cultured human endothelial cells.

Synonyms: Adipocyte FABP Inhibitor; Fatty Acid Binding Protein 4 Inhibitor; FABP4 Inhibitor

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Product Details of BMS-309403

CAS No. :300657-03-8
Formula : C31H26N2O3
M.W : 474.55
SMILES Code : O=C(O)COC1=CC(C2=CC=CC=C2N3N=C(C4=CC=CC=C4)C(C5=CC=CC=C5)=C3CC)=CC=C1
Synonyms :
Adipocyte FABP Inhibitor; Fatty Acid Binding Protein 4 Inhibitor; FABP4 Inhibitor
MDL No. :MFCD09991687
InChI Key :SJRVJRYZAQYCEE-UHFFFAOYSA-N
Pubchem ID :16122583

Safety of BMS-309403

GHS Pictogram:
Signal Word:Warning
Hazard Statements:H302-H315-H319-H335
Precautionary Statements:P261-P305+P351+P338

Isoform Comparison

Biological Activity

In Vitro:

Cell Line
Concentration Treated Time Description References
DRG neurons 10 µM 15 minutes BMS309403 inhibited CAY10455 uptake in DRG neurons, reducing AEA uptake Neurobiol Dis. 2013 Oct;58:19-28.
Human umbilical vein endothelial cells (HUVECs) 20 µM 24 hours BMS309403 significantly inhibited the tube formation, proliferation, migration, and invasion of HUVECs induced by rhFABP4 or M1-polarized macrophage supernatant. Bone Res. 2022 Jun 22;10(1):45.
Fibroblast-like synoviocytes (FLSs) 20 µM 24 hours BMS309403 significantly inhibited the proliferation, migration, and invasion of FLSs induced by rhFABP4 or M1-polarized macrophage supernatant. Bone Res. 2022 Jun 22;10(1):45.
SKOV3ip1 cells 20 µM 24 hours BMS309403 treatment resulted in cell cycle arrest, increasing the number of cells in the G1 phase and reducing the number of cells in the S phase. Cancer Res. 2020 Apr 15;80(8):1748-1761.
RBE cells 20 µM 24 hours BMS309403 significantly suppressed the adipose-induced CCA invasion and migration in vitro and reversed the effects of adipose tissue extracts on EMT-related protein expression. J Exp Clin Cancer Res. 2017 Dec 13;36(1):183.
Hccc-9810 cells 20 µM 24 hours BMS309403 significantly suppressed the adipose-induced migration and invasion of Hccc-9810 cells. J Exp Clin Cancer Res. 2017 Dec 13;36(1):183.
Human Microvascular Endothelial Cells (HMECs) 50 µM 24 hours BMS-309403 reversed the palmitate-induced reduction in eNOS phosphorylation and cGMP production, indicating its beneficial effect on endothelial function. Br J Pharmacol. 2011 Apr;162(7):1564-76.
HepG2 cells 10, 30, 50 µM 24 hours BMS309403 reversed the promoting effects of FABP4 on HepG2 cell proliferation and migration, and increased active caspase 3 expression. Oncogene. 2019 Apr;38(16):3033-3046.
HuH7 cells 10, 30, 50 µM 24 hours BMS309403 reversed the promoting effects of FABP4 on HuH7 cell proliferation. Oncogene. 2019 Apr;38(16):3033-3046.
Thp-1 cells 50 µM 24 hours Inhibition of A-FABP almost reversed PA-induced macrophage apoptosis, indicating that A-FABP plays a critical role in PA-induced macrophage apoptosis. Front Immunol. 2018 Jan 30;9:81.
BV-2 cells 50 µM 24 hours To evaluate the effect of BMS309403 on LPS-induced inflammatory response in BV-2 cells, results showed that BMS309403 significantly reduced ROS and TNF-α production. J Neuroimmune Pharmacol. 2023 Sep;18(3):448-461.
Primary mouse microglia 50 µM 24 hours To evaluate the effect of BMS309403 on LPS-induced inflammatory response in primary mouse microglia, results showed that BMS309403 significantly reduced TNF-α production. J Neuroimmune Pharmacol. 2023 Sep;18(3):448-461.
Mouse renal tubular epithelial cells (TCMK-1) 10 µM 30 minutes Inhibition of FABP4, alleviating LPS-induced inflammation and apoptosis Cell Death Dis. 2022 Apr 11;13(4):333.
Rat neutrophils 10 µM 30 minutes After BMS-309403 treatment, FABP4 expression in rat neutrophils decreased, and apoptosis was reduced. Cell Mol Life Sci. 2024 Oct 25;81(1):438.
Mouse neutrophils 10 µM 30 minutes After BMS-309403 treatment, FABP4 expression in mouse neutrophils decreased, and apoptosis was reduced. Cell Mol Life Sci. 2024 Oct 25;81(1):438.
C1498 cells 30 µM 48 hours BMS309403 treatment led to downregulation of DNMT1, reduction of global DNA methylation, and restoration of p15INK4B expression Leukemia. 2018 Apr;32(4):865-873.
MV4-11 cells 30 µM 48 hours BMS309403 treatment led to downregulation of DNMT1, reduction of global DNA methylation, and restoration of p15INK4B expression Leukemia. 2018 Apr;32(4):865-873.
Kasumi-1 cells 30 µM 48 hours BMS309403 treatment led to downregulation of DNMT1, reduction of global DNA methylation, and restoration of p15INK4B expression Leukemia. 2018 Apr;32(4):865-873.
Bone marrow-derived macrophages (BMDMs) 2.5 ng/ml 5 days To investigate the role of FABP4 in TGF-b1-induced transition of BMDMs into myofibroblasts, results showed that FABP4 deficiency significantly inhibited TGF-b1-induced a-SMA expression. Front Immunol. 2020 Sep 30;11:566535.
COS-7 cells 20–100 µM 5 minutes BMS-309403 significantly reduced AEA uptake and hydrolysis in COS-7 cells, with a maximal inhibition of 48%. Proc Natl Acad Sci U S A. 2009 Apr 14;106(15):6375-80.
N18TG2 cells 20–100 µM 5 minutes BMS-309403 significantly reduced AEA uptake and hydrolysis in N18TG2 cells, with a maximal inhibition of 57%. Proc Natl Acad Sci U S A. 2009 Apr 14;106(15):6375-80.
PE01 and PE04 cells 20 µM 72 hours BMS309403 significantly increased the sensitivity of PE04 cells to carboplatin. Cancer Res. 2020 Apr 15;80(8):1748-1761.

In Vivo:

Species
Animal Model
Administration Dosage Frequency Description References
Mice Apolipoprotein E-deficient mice (ApoE-/-) Oral gavage 15 mg/kg/day Once daily for 6 weeks BMS-309403 improved endothelium-dependent relaxations, increased phosphorylated and total eNOS levels, and reduced plasma triglyceride levels. Br J Pharmacol. 2011 Apr;162(7):1564-76.
Mice Syngeneic orthotopic mouse model Oral 20 mg/kg Six days a week for 4 weeks BMS309403 significantly reduced metastatic tumor burden and increased tumor sensitivity to carboplatin. Cancer Res. 2020 Apr 15;80(8):1748-1761.
C57BL/6J mice CLP or LPS-induced septic acute kidney injury model Oral 40 mg/kg/d Once daily for 3 days Inhibition of FABP4, alleviating septic acute kidney injury Cell Death Dis. 2022 Apr 11;13(4):333.
C57BL/6 mice Unilateral ureteral obstruction (UUO) model Oral 40 mg/kg/day Once daily, during the UUO surgery period To evaluate the effect of BMS-309403 on UUO-induced kidney fibrosis, the results showed that BMS-309403 significantly attenuated kidney fibrosis and lipid deposition. Cell Death Dis. 2021 Jun 3;12(6):572
BALB/c Nude mice Heterotopic and orthotopic xenografted model Intraperitoneal injection 45 mg/kg Twice a week for 3 weeks BMS309403 significantly reduced tumor growth in heterotopic and orthotopic xenografted models and increased tumor necrosis. Oncogene. 2019 Apr;38(16):3033-3046.
C57BL/6 J mice Antigen-induced arthritis (AIA) model Intraperitoneal injection 5 mg/kg Twice a week for 4 or 8 weeks BMS309403 significantly reduced FABP4 expression in synovial M1-polarized macrophages and serum, suppressed synovitis, angiogenesis, and cartilage degradation, thereby alleviating experimental RA progression. Bone Res. 2022 Jun 22;10(1):45.
C57BL/6 mice Cecal ligation and puncture (CLP)-induced sepsis model Intraperitoneal injection 5 mg/kg Administered 2 days before modeling BMS-309403 treatment exacerbated CLP-induced lung injury, while neutrophil depletion alleviated the promotion of ARDS development by BMS-309403. Cell Mol Life Sci. 2024 Oct 25;81(1):438.
C57BL/6 mice High-fat diet-induced steatotic liver transplantation model Intraperitoneal injection 5 mg/kg Single dose, 1 hour before transplantation To evaluate the protective effect of BMS-309403 on ischemia-reperfusion injury in the steatotic liver transplantation model, results showed that BMS-309403 reduced hepatocyte apoptosis, decreased serum transaminase levels, and alleviated oxidative stress damage. Cell Mol Life Sci. 2024 Feb 10;81(1):83
C57BL/6 mice Leukemia model Intraperitoneal injection 5 mg/kg and 10 mg/kg Initial dose of 5 mg/kg, leukemia cells injected 12 hours later, 3 additional doses within 3 days, followed by two doses of 10 mg/kg BMS309403 significantly reduced leukemic burden, prolonged survival time, and restored granulocytic differentiation of bone marrow cells Leukemia. 2018 Apr;32(4):865-873.
C57BL/6J mice Unilateral ureteral obstruction (UUO) model Oral 50 mg/kg/day Once daily for 7 days To investigate the effect of BMS309403 on attenuating renal fibrosis in the UUO model, results showed that BMS309403 significantly reduced renal interstitial inflammation and fibrosis. Front Immunol. 2020 Sep 30;11:566535.

Protocol

Bio Calculators
Preparing Stock Solutions 1mg 5mg 10mg

1 mM

5 mM

10 mM

2.11mL

0.42mL

0.21mL

10.54mL

2.11mL

1.05mL

21.07mL

4.21mL

2.11mL

Dissolving Methods
Please choose the appropriate dissolution scheme according to your animal administration guide.For the following dissolution schemes, clear stock solution should be prepared according to in vitro experiments, and then cosolvent should be added in turn:

in order to ensure the reliability of the experimental results, the clarified stock solution can be properly preserved according to the storage conditions; The working fluid for in vivo experiment is recommended to be prepared now and used on the same day;

The percentage shown in front of the following solvent refers to the volume ratio of the solvent in the final solution; If precipitation or precipitation occurs in the preparation process, it can be assisted by heating and/or ultrasound.
Protocol 1
Protocol 2

References

[1]Suhre K, Römisch-Margl W, et al. Identification of a potential biomarker for FABP4 inhibition: the power of lipidomics in preclinical drug testing. J Biomol Screen. 2011 Jun;16(5):467-75.

[2]Lan H, Cheng CC, et al. Small-molecule inhibitors of FABP4/5 ameliorate dyslipidemia but not insulin resistance in mice with diet-induced obesity. J Lipid Res. 2011 Apr;52(4):646-56.

[3]Mosińska P, Szczepaniak A, et al. Chain length of dietary fatty acids determines gastrointestinal motility and visceromotor function in mice in a fatty acid binding protein 4-dependent manner. Eur J Nutr. 2019 Sep 27.

[4]Okamura Y, Otani K, et al. Vasculo-protective effect of BMS-309403 is independent of its specific inhibition of fatty acid-binding protein 4. Pflugers Arch. 2017 Sep;469(9):1177-1188.

[5]Sulsky R, Magnin DR, Huang Y, Simpkins L, Taunk P, Patel M, Zhu Y, Stouch TR, Bassolino-Klimas D, Parker R, Harrity T, Stoffel R, Taylor DS, Lavoie TB, Kish K, Jacobson BL, Sheriff S, Adam LP, Ewing WR, Robl JA. Potent and selective biphenyl azole inhibitors of adipocyte fatty acid binding protein (aFABP). Bioorg Med Chem Lett. 2007 Jun 15;17(12):3511-5. doi: 10.1016/j.bmcl.2006.12.044. Epub 2006 Dec 21. PMID: 17502136.

[6]Furuhashi M, Tuncman G, Görgün CZ, Makowski L, Atsumi G, Vaillancourt E, Kono K, Babaev VR, Fazio S, Linton MF, Sulsky R, Robl JA, Parker RA, Hotamisligil GS. Treatment of diabetes and atherosclerosis by inhibiting fatty-acid-binding protein aP2. Nature. 2007 Jun 21;447(7147):959-65. doi: 10.1038/nature05844. Epub 2007 Jun 6. PMID: 17554340; PMCID: PMC4076119.

[7]Lin W, Huang X, Zhang L, Chen D, Wang D, Peng Q, Xu L, Li J, Liu X, Li K, Ding K, Jin S, Li J, Wu D. BMS309403 stimulates glucose uptake in myotubes through activation of AMP-activated protein kinase. PLoS One. 2012;7(8):e44570. doi: 10.1371/journal.pone.0044570. Epub 2012 Aug 31. PMID: 22952994; PMCID: PMC3432117.

[8]Lee MY, Li H, Xiao Y, Zhou Z, Xu A, Vanhoutte PM. Chronic administration of BMS309403 improves endothelial function in apolipoprotein E-deficient mice and in cultured human endothelial cells. Br J Pharmacol. 2011 Apr;162(7):1564-76. doi: 10.1111/j.1476-5381.2010.01158.x. PMID: 21175571; PMCID: PMC3057294.

 

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