DDR-TRK-1 (DDR1 inhibitor 6j)

IC50: 9.4 nM (DDR1).

DDR-TRK-1 is a promising candidate, with an IC ₅₀ value of 9.4 nM against DDR1. DDR-TRK-1 also exhibits reasonable pharmacokinetic (PK) properties, with an oral bioavailability of 66.8% and a T _1/2 value of 1.25 h at an oral dose of 20 mg/kg in rats. However, the area under concentration−time curve (AUC) value of DDR-TRK-1 in mice is obviously higher than that in rats, suggesting its good absorption property in mice. The DDR1 inhibition of DDR1-IN-3 is further validated by determining its binding affinity with the DDR1 protein. It is shown that DDR-TRK-1 bounds tightly to DDR1, with a binding constant (K _d ) value of 4.7 nM.

DDR-TRK-1 prevents these BLM-induced pathological changes in a dose-dependent manner. These results agree with the expression levels of fibrotic markers in lung tissue lysates, including fibronectin and α-smooth muscle actin (SMA). Further analyses also reveal that the administration of DDR-TRK-1 cause a dose-dependent suppression in the content of hydroxyproline, a unique amino acid found in collagen. The above data collectively indicate the promising therapeutic potential of DDR-TRK-1 against the BLM-induced pulmonary fibrosis.