Department of Chemistry and ∥Department of Molecular Therapeutics, Scripps Florida , Jupiter, Florida 33458, United States.
J Med Chem. 2013 Oct 10;56(19):7651-68. doi: 10.1021/jm401067s. Epub 2013 Sep 30.
A new series of 4-aminopyridyl-based lead inhibitors targeting Trypanosoma cruzi CYP51 (TcCYP51) has been developed using structure-based drug design as well as structure-property relationship (SPR) analyses. The screening hit starting point, LP10 (KD ≤ 42 nM; EC50 = 0.65 μM), has been optimized to give the potential leads 14t, 27i, 27q, 27r, and 27t, which have low-nanomolar binding affinity to TcCYP51 and significant activity against T. cruzi amastigotes cultured in human myoblasts (EC50 = 14-18 nM for 27i and 27r). Many of the optimized compounds have improved microsome stability, and most are selective against human CYPs 1A2, 2D6, and 3A4 (<50% inhibition at 1 μM). A rationale for the improvement in microsome stability and selectivity of inhibitors against human metabolic CYP enzymes is presented. In addition, the binding mode of 14t with the Trypanosoma brucei CYP51 (TbCYP51) orthologue has been characterized by X-ray structure analysis.
我们采用基于结构的药物设计和结构-性质关系（SPR）分析，开发了一系列以 4-氨基吡啶为基础的新型先导抑制剂，用于靶向克氏锥虫 CYP51（TcCYP51）。以 LP10（KD ≤ 42 nM；EC50 = 0.65 μM）为筛选起始点，经过优化得到潜在的先导化合物 14t、27i、27q、27r 和 27t，它们对 TcCYP51 具有低纳摩尔结合亲和力，对在人成肌细胞中培养的克氏锥虫无鞭毛体具有显著的活性（EC50 = 14-18 nM 用于 27i 和 27r）。许多优化的化合物具有改善的微粒体稳定性，并且大多数对人 CYP1A2、2D6 和 3A4 具有选择性（在 1 μM 时抑制率<50%）。本文提出了提高抑制剂对人代谢 CYP 酶的微粒体稳定性和选择性的原理。此外，通过 X 射线结构分析，还对 14t 与布氏锥虫 CYP51（TbCYP51）同源物的结合模式进行了表征。
