Liang Jun, Labadie Sharada, Zhang Birong, Ortwine Daniel F, Patel Snahel, Vinogradova Maia, Kiefer James R, Mauer Till, Gehling Victor S, Harmange Jean-Christophe, Cummings Richard, Lai Tommy, Liao Jiangpeng, Zheng Xiaoping, Liu Yichin, Gustafson Amy, Van der Porten Erica, Mao Weifeng, Liederer Bianca M, Deshmukh Gauri, An Le, Ran Yingqing, Classon Marie, Trojer Patrick, Dragovich Peter S, Murray Lesley
Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
Bioorg Med Chem Lett. 2017 Jul 1;27(13):2974-2981. doi: 10.1016/j.bmcl.2017.05.016. Epub 2017 May 5.
A high-throughput screening (HTS) of the Genentech/Roche library identified a novel, uncharged scaffold as a KDM5A inhibitor. Lacking insight into the binding mode, initial attempts to improve inhibitor potency failed to improve potency, and synthesis of analogs was further hampered by the presence of a C-C bond between the pyrrolidine and pyridine. Replacing this with a C-N bond significantly simplified synthesis, yielding pyrazole analog 35, of which we obtained a co-crystal structure with KDM5A. Using structure-based design approach, we identified 50 with improved biochemical, cell potency and reduced MW and lower lipophilicity (LogD) compared with the original hit. Furthermore, 50 showed lower clearance than 9 in mice. In combination with its remarkably low plasma protein binding (PPB) in mice (40%), oral dosing of 50 at 5mg/kg resulted in unbound C ∼2-fold of its cell potency (PC9 H3K4Me3 0.96μM), meeting our criteria for an in vivo tool compound from a new scaffold.
对基因泰克/罗氏文库进行的高通量筛选（HTS）确定了一种新型的、不带电荷的骨架作为KDM5A抑制剂。由于对结合模式缺乏了解，最初提高抑制剂效力的尝试未能成功，且吡咯烷和吡啶之间存在C-C键，这进一步阻碍了类似物的合成。用C-N键取代它显著简化了合成过程，得到了吡唑类似物35，我们获得了它与KDM5A的共晶体结构。使用基于结构的设计方法，我们确定了化合物50，与最初的命中化合物相比，其生化活性、细胞效力得到改善，分子量降低，亲脂性（LogD）降低。此外，化合物50在小鼠体内的清除率低于化合物9。结合其在小鼠体内极低的血浆蛋白结合率（PPB）（40%），以5mg/kg的剂量口服化合物50，导致游离药物浓度约为其细胞效力（PC9 H3K4Me3为0.96μM）的2倍，满足了我们对来自新骨架的体内工具化合物的标准。
