γ-内酰胺异羟肟酸作为肿瘤坏死因子α转换酶选择性抑制剂的发现：设计、合成及构效关系
Discovery of gamma-lactam hydroxamic acids as selective inhibitors of tumor necrosis factor alpha converting enzyme: design, synthesis, and structure-activity relationships.
作者信息
Duan James J-W, Chen Lihua, Wasserman Zelda R, Lu Zhonghui, Liu Rui-Qin, Covington Maryanne B, Qian Mingxin, Hardman Karl D, Magolda Ronald L, Newton Robert C, Christ David D, Wexler Ruth R, Decicco Carl P
机构信息
Discovery Chemistry, Bristol-Myers Squibb Company, Experimental Station, Wilmington, Delaware 19880-0500, USA.
出版信息
J Med Chem. 2002 Nov 7;45(23):4954-7. doi: 10.1021/jm0255670.
New gamma-lactam TACE inhibitors were designed from known MMP inhibitors. A homology model of TACE was built and examined to identify the S1' site as the key area for TACE selectivity over MMPs. Rational exploration of the P1'-S1' interactions resulted in the discovery of the 3,5-disubstituted benzyl ether as a TACE-selective P1' group. Further optimization led to the discovery of IK682 as a selective and orally bioavailable TACE inhibitor.
新型γ-内酰胺TACE抑制剂是基于已知的MMP抑制剂设计而成。构建并检测了TACE的同源模型，以确定S1'位点是TACE相对于MMPs具有选择性的关键区域。对P1'-S1'相互作用进行合理探索，发现3,5-二取代苄基醚是一种TACE选择性P1'基团。进一步优化后发现IK682是一种选择性且口服生物可利用的TACE抑制剂。
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