Discoidin domain receptor 1 (DDR1) is a collagen-activated receptor tyrosine kinase and an attractive anti-fibrotic target. To identify novel DDR1 inhibitors, we used an integrated lead-finding approach relying in parallel on structure-based hybrid design and a focused screening campaign. Combining structural elements from both approaches allowed us to quickly overcome several compound liabilities and optimize the hits to advanced lead compounds. Despite a very high sequence conservation between DDR1 and DDR2, we were able to identify potent DDR1 inhibitors with close to 1000-fold selectivity against DDR2 as well as good selectivity against the full kinome. Exploitation of a DDR1 selectivity pocket detected by structural bioinformatics was crucial in the optimization process. Compounds with very high selectivity suffered from poor metabolic stability in rodents but may serve as useful DDR1-selective in vitro tool molecules.Graphical Abstract