2. Academic Validation
  3. Structure-Based Optimization and Biological Evaluation of Potent and Selective MMP-7 Inhibitors for Kidney Fibrosis

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

  • J Med Chem. 2023 Oct 20. doi: 10.1021/acs.jmedchem.3c01166.
Kumi Abe-Sato 1,  Hideaki Tabuse 1,  Harumi Kanazawa 1,  Masafumi Kamitani 2,  Mayumi Endo 2,  Seiken Tokura 2,  Satoshi Wakabayashi 3,  Tohru Yahara 3,  Takuya Takeda 4,  Kosuke Hitaka 4,  Emi Gunji 4,  Naoki Kojima 4,  Yusuke Oka 1
Affiliations

Affiliations

  • 1 Medicinal Chemistry Laboratories, Taisho Pharmaceutical Co., Ltd., 1-403, Yoshino-Cho, Kita-Ku, Saitama, Saitama 331-9530, Japan.
  • 2 Discovery Technologies Laboratories, Taisho Pharmaceutical Co., Ltd., 1-403, Yoshino-Cho, Kita-Ku, Saitama, Saitama 331-9530, Japan.
  • 3 Drug Metabolism and Pharmacokinetics Laboratories, Taisho Pharmaceutical Co., Ltd., 1-403, Yoshino-Cho, Kita-Ku, Saitama, Saitama 331-9530, Japan.
  • 4 Pharmacology Laboratories, Taisho Pharmaceutical Co., Ltd., 1-403, Yoshino-Cho, Kita-Ku, Saitama, Saitama 331-9530, Japan.
PMID: 37861435 DOI: 10.1021/acs.jmedchem.3c01166
Abstract

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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-156430
    99.93%, MMP-7抑制剂
    MMP
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