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

• Published in: Journal of medicinal chemistry 2023-11, Vol.66 (21), p.14653-14668
• Main Authors: Abe-Sato, Kumi, Tabuse, Hideaki, Kanazawa, Harumi, Kamitani, Masafumi, Endo, Mayumi, Tokura, Seiken, Wakabayashi, Satoshi, Yahara, Tohru, Takeda, Takuya, Hitaka, Kosuke, Gunji, Emi, Kojima, Naoki, Oka, Yusuke
• Format: Article
• Language: English
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.3c01166

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.