Journal of Medicinal Chemistry p. 608 - 626 (2017)
Update date:2022-08-15
Topics:
Nara, Hiroshi
Kaieda, Akira
Sato, Kenjiro
Naito, Takako
Mototani, Hideyuki
Oki, Hideyuki
Yamamoto, Yoshio
Kuno, Haruhiko
Santou, Takashi
Kanzaki, Naoyuki
Terauchi, Jun
Uchikawa, Osamu
Kori, Masakuni
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.
View Morewebsite:http://www.lonwinchem.com
Contact:Tel: 86-21-59858395
Address:No#966,Huaxu Road,Shanghai 201702,P.R.China
Hangzhou Haiqiang Chemical Co.,Ltd.
Contact:+86-571-86960370
Address:Add: 5/F, Around Town North Road,No. 10, Hangzhou, Zhejiang,China
JOY (TIANJIN) TECHNOLOGY AND DEVELOPMENT CO., LTD.
Contact:+86-22-66666666
Address:Tianjin
Jiangsu Chunjiang AgroChemical Co.,Ltd.
Contact:+86-13817348163
Address:Panjiawan 84, Zhixi Town, Jintan City, China
Shandong Jiulong Hisince Pharmaceutical Co.,Ltd.
Contact:+86-15853188990
Address:Huadian Pioneer Park, Huadian Township, Qihe County, Dezhou City, Shandong, P.R.China
Doi:10.1007/BF00474099
()Doi:10.1007/BF00474096
()Doi:10.1515/znb-2014-0178
(2015)Doi:10.1016/S0022-328X(00)82811-9
(1980)Doi:10.1016/j.bmcl.2004.01.099
(2004)Doi:10.1021/jo01331a017
(1979)