Pfizer Global Research and Development, Eastern Point Road, Groton, CT 06340, USA.
Bioorg Med Chem Lett. 2010 Apr 1;20(7):2383-8. doi: 10.1016/j.bmcl.2009.04.091. Epub 2009 Apr 24.
Screening Pfizer's compound library resulted in the identification of weak acetyl-CoA carboxylase inhibitors, from which were obtained rACC1 CT-domain co-crystal structures. Utilizing HTS hits and structure-based drug discovery, a more rigid inhibitor was designed and led to the discovery of sub-micromolar, spirochromanone non-specific ACC inhibitors. Low nanomolar, non-specific ACC-isozyme inhibitors that exhibited good rat pharmacokinetics were obtained from this chemotype.
筛选辉瑞化合物库导致发现了弱乙酰辅酶 A 羧化酶抑制剂，从中获得了 rACC1 CT 结构域共晶结构。利用高通量筛选和基于结构的药物发现，设计了更刚性的抑制剂，并发现了亚毫摩尔的螺环色满酮非特异性 ACC 抑制剂。从这种化学类型中获得了具有良好大鼠药代动力学的低纳摩尔非特异性 ACC 同工酶抑制剂。
