Design, synthesis and evaluation of novel UDCA-aminopyrimidine hybrids as ATX inhibitors for the treatment of hepatic and pulmonary fibrosis.

To discover novel anti-fibrotic agents, a series of UDCA-aminopyrimidine hybrids were designed and synthesized as potent ATX inhibitors by molecular hybridization strategy. The ATX inhibitory activities of all synthesized compounds were evaluated using the LPC choline release assay. The preliminary structure-activity relationship was concluded. Among them, 12a and 12h exhibited the strongest ATX inhibitory activities with IC 50 values of 7.62 ± 0.62 and 7.51 ± 0.72 nM respectively, which were 9-fold more effective than the positive control drug GLPG-1690. Molecular docking studies revealed that 12a and 12h occupied the hydrophobic pocket and tunnel of the ATX binding site. The cytotoxicity assay of 12a and 12h revealed that they had no obvious toxicity at concentrations up to 80 μM, therefore their anti-hepatic fibrosis and anti-pulmonary fibrosis activities were further investigated. The results suggested that 12a and 12h significantly decreased the gene and protein expression of α-SMA, COL1A1 and FN in both TGF-β1-induced HSC-LX2 and CCC-HPF-1 cells. In addition, 12a and 12h significantly inhibited cells migration in both TGF-β1-induced HSC-LX2 and CCC-HPF-1 cells. Preliminary mechanistic studies indicated that 12a and 12h exerted anti-hepatic fibrosis and anti-pulmonary fibrosis effects by inhibiting the TGF-β/Smad signaling pathway. Overall, our findings suggested that 12a and 12h might be two promising anti-fibrotic agents, or might serve as two new lead compounds for the further development of anti-fibrotic agents. [Display omitted] • Novel ursodeoxycholic acid (UDCA)-aminopyrimidine hybrids were synthesized. • Compounds 12a and 12h displayed significant ATX inhibitory activity. • Compounds 12a and 12h significantly decreased the gene and protein expression of α-SMA, COL1A1 and FN. • Compounds 12a and 12h markedly inhibited TGF-β1-induced migration of HSC-LX2 and CCC-HPF-1 cells. • Compound 12a and 12h exerted their anti-fibrotic activities through the inhibition. [ABSTRACT FROM AUTHOR]