Structure-Based Optimization and Biological Evaluation of Potent and Selective MMP‑7 Inhibitors for Kidney Fibrosis

Matrix metalloproteinase-7 (MMP-7) has been shown to
play important
roles in pathophysiological processes involved in the development/progression
of diseases such as cancer and fibrosis. We discovered selective MMP-7
inhibitors composed of arylsulfonamide, carboxylate, and short peptides
by a molecular hybridization approach. These compounds interacted
with MMP-7 via multiple hydrogen bonds in the cocrystal structures.
To obtain compounds for in vivo evaluation, we attempted
structural optimization, particularly targeting Tyr167 at the S3 subsite
through structure-based drug design, and identified compound 15 as showing improved MMP-7 potency and MMP subtype selectivity.
A novel π–π stacking interaction with Tyr167 was
achieved when 4-pyridylalanine was introduced as the P3 residue. Compound 15 suppressed the progression of kidney fibrosis in a dose-dependent
manner in a mouse model of unilateral ureteral obstruction. Thus,
we demonstrated, for the first time, that potent and selective MMP-7
inhibitors could prevent the progression of kidney fibrosis.