Medicinal Chemistry, deCODE Chemistry, Inc., 2501 Davey Road, Woodridge, Illinois 60517, USA.
J Med Chem. 2010 Jan 28;53(2):573-85. doi: 10.1021/jm900838g.
Both in-house human genetic and literature data have converged on the identification of leukotriene 4 hydrolase (LTA(4)H) as a key target for the treatment of cardiovascular disease. We combined fragment-based crystallography screening with an iterative medicinal chemistry effort to optimize inhibitors of LTA(4)H. Ligand efficiency was followed throughout our structure-activity studies. As applied within the context of LTA(4)H inhibitor design, the chemistry team was able to design a potent compound 20 (DG-051) (K(d) = 26 nM) with high aqueous solubility (>30 mg/mL) and high oral bioavailability (>80% across species) that is currently undergoing clinical evaluation for the treatment of myocardial infarction and stroke. The structural biology-chemistry interaction described in this paper provides a sound alternative to conventional screening techniques. This is the first example of a gene-to-clinic paradigm enabled by a fragment-based drug discovery effort.
内源性人类遗传学和文献资料都集中在白三烯 4 水解酶（LTA(4)H）的鉴定上，认为它是治疗心血管疾病的关键靶点。我们将基于片段的晶体学筛选与迭代药物化学研究相结合，以优化 LTA(4)H 的抑制剂。在整个结构活性研究中，我们都跟踪了配体效率。在 LTA(4)H 抑制剂设计的背景下，化学团队能够设计出一种有效的化合物 20（DG-051）（K(d) = 26 nM），其水溶性高（>30 mg/mL），口服生物利用度高（跨物种>80%），目前正在进行临床试验，用于治疗心肌梗死和中风。本文描述的结构生物学与化学的相互作用为传统筛选技术提供了一种合理的替代方法。这是首次通过基于片段的药物发现工作实现从基因到临床的范例。
