Development of Thioaryl-Based Matrix Metalloproteinase-12 Inhibitors with Alternative Zinc-Binding Groups: Synthesis, Potentiometric, NMR, and Crystallographic Studies

Matrix metalloproteinase-12
(MMP-12) selective inhibitors could
play a role in the treatment of lung inflammatory and cardiovascular
diseases. In the present study, the previously reported 4-methoxybiphenylsulfonyl
hydroxamate and carboxylate based inhibitors (1b and 2b) were modified to enhance their selectivity for MMP-12.
In the newly synthesized thioaryl derivatives, the nature of the zinc
binding group (ZBG) and the sulfur oxidation state were changed. Biological
assays carried out in vitro on human MMPs with the resulting compounds
led to identification of a sulfide, 4a, bearing an N-1-hydroxypiperidine-2,6-dione (HPD) group as new ZBG.
Compound 4a is a promising hit compound since it displayed
a nanomolar affinity for MMP-12 with a marked selectivity over MMP-9,
MMP-1, and MMP-14. Solution complexation studies with Zn2+ were performed to characterize the chelating abilities of the new
compounds and confirmed the bidentate binding mode of HPD derivatives.
X-ray crystallography studies using MMP-12 and MMP-9 catalytic domains
were carried out to rationalize the biological results.