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DDR1-IN-3 is a selective Discoidin Domain Receptor 1 (DDR1) inhibitor, with an IC50 value of 9.4 nM.

DDR1-IN-3 is a promising candidate, with an IC50 value of 9.4 nM against DDR1. DDR1-IN-3 also exhibits reasonable pharmacokinetic (PK) properties, with an oral bioavailability of 66.8% and a T1/2 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 DDR1-IN-3 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 DDR1-IN-3 bounds tightly to DDR1, with a binding constant (Kd) value of 4.7 nM[1].

DDR1-IN-3 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 DDR1-IN-3 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 DDR1-IN-3 against the BLM-induced pulmonary fibrosis[1].

[1]. Zhen Wang, et al. Structure-Based Design of Tetrahydroisoquinoline-7-carboxamides as Selective Discoidin Domain Receptor 1 (DDR1) Inhibitors. J Med Chem. 2016 Jun 23; 59(12): 5911-5916.

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