Fig. 1

Structure and pharmacological profile of partial FXR agonist 1. a Constitution of 1 and endogenous agonist CDCA (2). b Dose-response curves of partial agonist 1, endogenous agonist 2 and ivermectin in a BSEP response element driven full-length FXR reporter gene assay. 1 partially activates FXR with an EC₅₀ value of 0.35 ± 0.06 µM and 21.1 ± 0.5% relative efficacy compared to the synthetic agonist GW4064 (3 µM). 1 also partially represses GW4064-induced FXR activation with an IC₅₀ value of 10.9 ± 0.2 µM to 26 ± 2% relative activation. CDCA (2) behaves as weakly potent (EC₅₀ = 4.0 ± 0.2 µM) agonist. Ivermectin has partial FXR agonistic activity (EC₅₀ = 0.060 ± 0.007 µM, 26 ± 1% rel. activation) and suppresses GW4064-induced FXR activation (IC₅₀ = 0.80 ± 0.16 µM, 22 ± 6% rel. act.). Results are mean ± SD, n = 3. c Partial agonistic activity of 1 was also observed in a hybrid Gal4-FXR reporter gene assay. d Profiling of 1 on NRs in hybrid reporter gene assays. Results are mean ± SEM, n = 3. e In vitro toxicity of 1 in HepG2 cells: 1 exhibits no acute toxicity in vitro up to 100 µM concentration. Results are mean ± SEM, n = 4. f In vitro metabolism analysis: 1 comprises good stability versus microsomal degradation with >60% of the parent compound remaining after 60 min. incubation. Results are mean ± SEM, n = 4. g Pharmacokinetic profile of 1 in C57BL/6j mice: With high oral bioavailability and a half-life of more than 2 h, 1 is suitable for in vivo studies. Results are mean ± SEM, n = 3. h Profiling of the effects of 1 on FXR regulated gene expression: Compared to endogenous FXR agonist CDCA, 1 partially induced FXR regulated genes in HepG2 cells (BSEP, SHP, CYP7A1, OSTα) and in HT-29 cells (IBABP, FGF19). Results are mean ± SEM, n = 3. i Hepatic mRNA levels of FXR-regulated genes upon treatment with 1 in mice: In mouse livers, 1 caused partial induction of SHP and partial repression of CYP7A1 compared to CDCA confirming its partial agonistic properties in vivo. Results are mean ± SEM, n = 3. Statistical significance was analysed by two-sided student’s t-test. ^#p < 0.1, *p < 0.05, **p < 0.01, ***p < 0.001 vs. 0.1% DMSO or as indicated. Source data are provided as a Source Data file