Advancement of DDR1 and DDR2 Inhibitors: Therapeutic Potential of Bioactive Compounds, Designing Strategies, and Structure‐Activity Relationship (SAR)

Abstract DDR1 and DDR2 are nonintegrin collagen receptors in the receptor tyrosine kinase family. Both DDRs bind to various collagen types and perform crucial functions in embryo development. DDRs are different from other receptor tyrosine kinases due to their interaction with extracellular matrix components and unusual activation kinetics. DDR regulates cell migration, survival, proliferation, differentiation, and extracellular matrix remodeling. Dysregulated DDR function is linked to the advancement of several human illnesses, including fibrosis, arthritis, neurodegenerative diseases, and cancer. DDRs play a vital role in disease progression and development. Therefore, the use of DDR inhibitors represents a promising therapeutic strategy, particularly for disorders with limited therapy alternatives. In recent years, DDRs have been regarded as attractive targets for drug development, as evidenced by a significant rise in research in this field. The current review illustrates about recent advancement of small molecules, their designing strategies and structure‐activity relationship. The DDR inhibitors can contain various core structures such as pyrimidine, phthalazine, pyrazole, pyrazine, imidazo[1,2‐ a ]sspyrazine, quinazoline, and thieno[3,2‐ b ]pyridin‐7‐yl derivatives. Furthermore, based on the constructive analysis of the published derivatives, we found that the majority of the powerful compounds have a similar scaffold (amide linker, hydrophobic tail, hinge binder with or without spacer). Among the different literature, the most potent compounds 4 ( imidazo[1,2‐ a ]pyrazine ) , 5 (pyridine), 19 (pyridine), and 24 (quinazoline) displayed potent activity against DDR1 with IC 50 values ranging from 2.26 – 4.67 nM, while DDR2 IC 50 values ranging from 3.2 – 7.29 nM. This approach will help medicinal chemists to refine and develop novel small molecules targeting DDR1 and DDR2.