BMS-986339

BMS-986339 is an orally active, potent FXR agonist. BMS-986339 forms H-bond with His298 and ASN287 residues. BMS-986339 can be used in the research of primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), and nonalcoholic steatohepatitis (NASH), anti-fibrosis[1].

Signaling Pathways >> Metabolic Enzyme/Protease >> FXR

Signaling Pathways >> Metabolic Enzyme/Protease >> Cytochrome P450

Research Areas >> Metabolic Disease

CYP2C8:8 μM (IC50)

CYP2C9:13.5 μM (IC50)

BMS-986339 (compound 32, 0.1 nM-10 μM, 24 h) reduces activation of genes expressing BSEP (bile salt export pump) in Huh-7 cells, and FGF19 in hepatocytes[1]. BMS-986339 inhibits cytochrome P450 activity (IC50: 8 μM (CYP2C8), 13.5 μM (CYP2C9)), and inhibits hERG channel in a patch clamp assay (IC50: 4.5 μM)[1]. BMS-986339 inhibits transporters OATP1B3 and BSEP with IC50 values of 1.44 and 1.5 μM, and hUGT1A1 (IC50: 4.85 μM)[1].

BMS-986339 (compound 32, p.o., 10 mg/kg, once daily for 9 days) induces Fgf15 production, and shows antifibrotic efficacy in mouse bile duct ligation (BDL) model[1]. BMS-986339 (p.o. or i.v., 5 mg/kg or 1 mg/kg) exhibits low clearance and a long elimination half-life in mice and rats[1]. Animal Model: Mouse bile duct ligation (BDL) model[1] Dosage: 0.3, 1, 3, and 10 mg/kg, once daily for 9 days. Administration: Oral administration Result: Induced Fgf15 and SHP (small heterodimer partner) gene expression to a similar extent in the ileum. Decreased the ratio of hydroxyproline to the total protein content, and decreased the collagen levels. Animal Model: Male C57BL6 mice, male Sprague-Dawley rat (pharmacokinetic assay)[1] Dosage: 5 mg/kg or 1 mg/kg Administration: Oral administration, intravenous injection Result: Pharmacokinetic profile of BMS-986339 (compound 32). parameter male C57BL6 mice male Sprague-Dawley rat dose (mg/kg) i.v. 1 1 dose (mg/kg) p.o. 5 2 Vss (L/kg) i.v. 2.2 5.2 AUCtotal (μM•h) i.v. 16.4 6.6 AUCtotal (μM•h) p.o. 56.6 5.8 t1/2 h (i.v.) 16 18 Fp.o. 69 40

[1]. Susheel J Nara, et al. Discovery of BMS-986339, a Pharmacologically Differentiated Farnesoid X Receptor Agonist for the Treatment of Nonalcoholic Steatohepatitis. J Med Chem. 2022 Jul 14;65(13):8948-8960.