肿瘤坏死因子-α转化酶（TACE）的强效、极具选择性、口服生物可利用的抑制剂：新型2-取代-1H-苯并[d]咪唑-1-基）甲基）苯甲酰胺P1'取代基
Potent, exceptionally selective, orally bioavailable inhibitors of TNF-alpha Converting Enzyme (TACE): novel 2-substituted-1H-benzo[d]imidazol-1-yl)methyl)benzamide P1' substituents.
作者信息
Ott Gregory R, Asakawa Naoyuki, Lu Zhonghui, Anand Rajan, Liu Rui-Qin, Covington Maryanne B, Vaddi Krishna, Qian Mingxin, Newton Robert C, Christ David D, Trzaskos James M, Duan James J-W
机构信息
Departments of Discovery Chemistry and Discovery Biology, Bristol-Myers Squibb Research and Development, Rte 206 and Province Line Road, Princeton, NJ 08543, USA.
出版信息
Bioorg Med Chem Lett. 2008 Mar 1;18(5):1577-82. doi: 10.1016/j.bmcl.2008.01.075. Epub 2008 Jan 26.
Novel ((2-substituted-1H-benzo[d]imidazol-1-yl)methyl)benzamides were found to be excellent P1' substituents in conjunction with unique constrained beta-amino hydroxamic acid scaffolds for the discovery of potent selective inhibitors of TNF-alpha Converting Enzyme (TACE). Optimized examples proved potent for TACE, exceptionally selective over a wide panel of MMP and ADAM proteases, potent in the suppression of LPS-induced TNF-alpha in human whole blood and orally bioavailable.
新型（(2-取代-1H-苯并[d]咪唑-1-基)甲基）苯甲酰胺被发现是优异的P1'取代基，与独特的受限β-氨基异羟肟酸支架相结合，用于发现肿瘤坏死因子-α转化酶（TACE）的强效选择性抑制剂。优化后的实例证明对TACE具有强效，对多种基质金属蛋白酶（MMP）和A Disintegrin And Metalloprotease（ADAM）蛋白酶具有极高的选择性，在抑制人全血中脂多糖诱导的肿瘤坏死因子-α方面具有强效，且口服生物利用度良好。
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