Andrews David M, Stokes Elaine S E, Carr Greg R, Matusiak Zbigniew S, Roberts Craig A, Waring Michael J, Brady Madeleine C, Chresta Christine M, East Simon J
Cancer and Infection Research, AstraZeneca, Mereside, Alderley Park, Macclesfield SK10 4TG, UK.
Bioorg Med Chem Lett. 2008 Apr 15;18(8):2580-4. doi: 10.1016/j.bmcl.2008.03.041. Epub 2008 Mar 16.
A lead benzamide, 3, was identified as a potent and low molecular weight histone deacetylase (HDAC) inhibitor. Optimization led to 16d, demonstrating an excellent balance of efficacy and non-efficacy properties, along with very desirable in vivo DMPK. The final compounds presented are >1000-fold more potent than the initial screen hit, an improvement in potency which was achieved with a concomitant significant improvement in all the main non-efficacy properties.
一种先导苯甲酰胺化合物3被鉴定为一种强效且低分子量的组蛋白去乙酰化酶（HDAC）抑制剂。经过优化得到了16d，它在疗效和非疗效特性之间展现出了极佳的平衡，同时还具有非常理想的体内药物代谢动力学性质。最终呈现的化合物比最初筛选得到的活性化合物的活性高1000倍以上，在活性上的这种提高伴随着所有主要非疗效特性的显著改善。
