1 research outputs found
Discovery of Novel, Highly Potent, and Selective Matrix Metalloproteinase (MMP)-13 Inhibitors with a 1,2,4-Triazol-3-yl Moiety as a Zinc Binding Group Using a Structure-Based Design Approach
On the basis of a
superposition study of X-ray crystal structures
of complexes of quinazoline derivative <b>1</b> and triazole
derivative <b>2</b> with matrix metalloproteinase (MMP)-13 catalytic
domain, a novel series of fused pyrimidine compounds which possess
a 1,2,4-triazol-3-yl group as a zinc binding group (ZBG) was designed.
Among the herein described and evaluated compounds, <b>31f</b> exhibited excellent potency for MMP-13 (IC<sub>50</sub> = 0.036
nM) and selectivities (greater than 1,500-fold) over other MMPs (MMP-1,
-2, -3, -7, -8, -9, -10, and -14) and tumor necrosis factor-α
converting enzyme (TACE). Furthermore, the inhibitor was shown to
protect bovine nasal cartilage explants against degradation induced
by interleukin-1 and oncostatin M. In this article, we report the
discovery of extremely potent, highly selective, and orally bioavailable
fused pyrimidine derivatives that possess a 1,2,4-triazol-3-yl group
as a novel ZBG for selective MMP-13 inhibition