Flipo Marion, Charton Julie, Hocine Akila, Dassonneville Sandrine, Deprez Benoit, Deprez-Poulain Rebecca
INSERM U761 Biostructures and Drug Discovery, Univ Lille Nord de France, Lille F-59006, France.
J Med Chem. 2009 Nov 12;52(21):6790-802. doi: 10.1021/jm900648x.
Hydroxamates are valuable tools for chemical biology as well as interesting leads for medicinal chemistry. Although many hydroxamates display nanomolar activities against metalloproteases, only three hydroxamates have reached the market, among which is the HDAC inhibitor vorinostat. Failures in development are generally attributed to lack of selectivity, toxicity, or poor stability. To help medicinal chemists with respect to plasma stability, we have performed the first and preliminary study on structure-plasma stability for hydroxamates. We define some structural rules to predict or improve the plasma stability in the preclinical stage.
异羟肟酸是化学生物学的重要工具，也是药物化学中有趣的先导化合物。尽管许多异羟肟酸对金属蛋白酶表现出纳摩尔级别的活性，但只有三种异羟肟酸已上市，其中包括组蛋白去乙酰化酶（HDAC）抑制剂伏立诺他。研发失败通常归因于缺乏选择性、毒性或稳定性差。为了帮助药物化学家提高血浆稳定性，我们首次对异羟肟酸的结构与血浆稳定性进行了初步研究。我们定义了一些结构规则，以便在临床前阶段预测或提高血浆稳定性。
