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Publication Abstract from PubMed

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 pi-pi 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.

Structure-Based Optimization and Biological Evaluation of Potent and Selective MMP-7 Inhibitors for Kidney Fibrosis.,Abe-Sato K, Tabuse H, Kanazawa H, Kamitani M, Endo M, Tokura S, Wakabayashi S, Yahara T, Takeda T, Hitaka K, Gunji E, Kojima N, Oka Y J Med Chem. 2023 Oct 20. doi: 10.1021/acs.jmedchem.3c01166. PMID:37861435^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.