Discovery of Aryloxyphenyl–Heptapeptide Hybrids as Potent and Selective Matrix Metalloproteinase‑2 Inhibitors for the Treatment of Idiopathic Pulmonary Fibrosis

Matrix
metalloproteinase-2 (MMP2) is a zinc-dependent endopeptidase
that plays important roles in the degradation of extracellular matrix
proteins. MMP2 is considered to be an attractive target for the treatment
of various diseases such as cancer, arthritis, and fibrosis. In this
study, we have developed a novel class of MMP2-selective inhibitors
by hybridizing the peptide that binds to a zinc ion and S2–S5
pockets with small molecules that bind to the S1′ pocket. Structural
modifications based on X-ray crystallography revealed that the introduction
of 2,4-diaminobutanoic acid (Dab) at position 4 dramatically enhanced
MMP2 selectivity by forming an electrostatic interaction with Glu130.
After improving the metabolic and chemical stability, TP0556351 (9) was identified. It exhibited potent MMP2 inhibitory activity
(IC50 = 0.20 nM) and extremely high selectivity. It suppressed
the accumulation of collagen in a bleomycin-induced idiopathic pulmonary
fibrosis model in mice, demonstrating the efficacy of MMP2-selective
inhibitors for fibrosis.