Pfizer Global Research and Development, La Jolla Laboratories, 10770 Science Center Drive, San Diego, California 92121, USA.
J Med Chem. 2010 Jan 14;53(1):499-503. doi: 10.1021/jm901209q.
The discovery and optimization of potency and metabolic stability of a novel class of dihyroxyphenylisoindoline amides as Hsp90 inhibitors are presented. Optimization of a screening hit using structure-based design and modification of log D and chemical structural features led to the identification of a class of orally bioavailable non-quinone-containing Hsp90 inhibitors. This class is exemplified by 14 and 15, which possess improved cell potency and pharmacokinetic profiles compared with the original screening hit.
本文介绍了一类新型二羟苯基异吲哚酰胺类 Hsp90 抑制剂的效力和代谢稳定性的发现和优化。通过基于结构的设计和对 log D 值及化学结构特征的修饰，对筛选出的苗头化合物进行优化，得到了一类口服生物利用度的非醌类 Hsp90 抑制剂。该类化合物以 14 和 15 为代表，与原始筛选出的苗头化合物相比，它们具有更好的细胞效力和药代动力学特性。
