Design of MMP-1 inhibitors via SAR transfer and experimental validation

New matrix metalloproteinase 1 (MMP-1) inhibitors were predicted using the structure-activity relationship (SAR) transfer method based on a series of analogues of kinesin-like protein 11 (KIF11) inhibitors. Compounds 5-7 predicted to be highly potent against MMP-1 were synthesized and tested for MMP-1 inhibitory activity. Among these, compound 6 having a Cl substituent at the R1 site was found to possess ca. 3.5 times higher inhibitory activity against MMP-1 than the previously reported compound 4. The observed potency was consistent with the presence of an SAR transfer event between analogous MMP-1 and KIF11 inhibitors. Pharmacophore fitting revealed that the higher inhibitory activity of compound 6 compared to compound 4 against MMP-1 might be due to a halogen bond interaction between the Cl substituent of compound 6 and residue ARG214 of MMP-1.