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
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- 作者：Hiroshi NaraAkira Kaieda ; Kenjiro Sato ; Takako Naito ; Hideyuki Mototani ; Hideyuki Oki ; Yoshio Yamamoto ; Haruhiko Kuno ; Takashi Santou ; Naoyuki Kanzaki ; Jun Terauchi ; Osamu Uchikawa ; Masakuni Kori
- 刊名：Journal of Medicinal Chemistry
- 出版年：2017
- 出版时间：January 26, 2017
- 年：2017
- 卷：60
- 期：2
- 页码：608-626
- 全文大小：838K
- ISSN：1520-4804
文摘
On the basis of a superposition study of X-ray crystal structures of complexes of quinazoline derivative 1 and triazole derivative 2 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, 31f exhibited excellent potency for MMP-13 (IC50 = 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.