| In Vitro | In vitro activity: Tropifexor (compound 1) is a novel and highly potent agonist of FXR with an EC50 of 0.2 nM. Robust induction of both BSEP and SHP genes is observed in primary cells by Tropifexor in a concentration-dependent manner. BSEP induction above vehicle (DMSO) control is observed at concentrations as low as 1 nM, while strong induction of SHP (15-fold above vehicle) is observed at 10 nM and modest induction of SHP at 1 nM (3-fold).
Kinase Assay: Tropifexor is a novel and highly potent agonist of FXR with an EC50 of 0.2 nM.
Cell Assay: |
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| In Vivo | Tropifexor (compound 1) demonstrates highly potent induction of SHP and FGF15 in the ileum as doses as low as 0.1 mg/kg. In the liver, robust induction of SHP is observed at 0.01 mg/kg of Tropifexor with maximal levels of gene induction achieved at 0.3 mg/kg. Expression of CYP8B1 mRNA following 14 day treatment with Tropifexor is already apparent at the lowest dose (0.003 mg/kg), and CYP8B1 gene expression is fully repressed at doses above 0.03 mg/kg. Treatment of rats with Tropifexor exhibits a clear dose-dependent increase in plasma FGF15 protein, with maximal levels of FGF15 detected at 7 h postdose. Treatment with Tropifexor for 14 days produces a robust dose-dependent reduction in serum triglycerides and reaches a maximal response with a 0.3 mg/kg dose, resulting in a decrease of triglyceride levels to approximately 79% below the vehicle control group. |
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| Animal model | Adult male wild-type Sprague-Dawley rats |
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| Formulation & Dosage | Dissolved 0.5% methylcellulose, 0.5% Tween80, 99% water, suspension; 0.03, 0.1, 0.3, and 1.0 mg/kg; Oral |
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| References | J Med Chem. 2017 Dec 28;60(24):9960-9973; Therap Adv Gastroenterol. 2017 Oct; 10(10): 791–803. |
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