Department of Chemistry, Heart Failure Disease Performance Unit, Metabolic Pathways and Cardiovascular Therapeutic Area Unit, GlaxoSmithKline, 709 Swedeland Road, King of Prussia, PA 19406, USA.
Bioorg Med Chem Lett. 2013 Jun 15;23(12):3584-8. doi: 10.1016/j.bmcl.2013.04.019. Epub 2013 Apr 16.
1-(1,3,5-Triazin-yl)piperidine-4-carboxamide inhibitors of soluble epoxide hydrolase were identified from high through-put screening using encoded library technology. The triazine heterocycle proved to be a critical functional group, essential for high potency and P450 selectivity. Phenyl group substitution was important for reducing clearance, and establishing good oral exposure. Based on this lead optimization work, 1-[4-methyl-6-(methylamino)-1,3,5-triazin-2-yl]-N-{[[4-bromo-2-(trifluoromethoxy)]-phenyl]methyl}-4-piperidinecarboxamide (27) was identified as a useful tool compound for in vivo investigation. Robust effects on a serum biomarker, 9, 10-epoxyoctadec-12(Z)-enoic acid (the epoxide derived from linoleic acid) were observed, which provided evidence of robust in vivo target engagement and the suitability of 27 as a tool compound for study in various disease models.
1-(1,3,5-三嗪基)哌啶-4-甲酰胺类可溶型环氧化物水解酶抑制剂是通过采用编码文库技术的高通量筛选发现的。三嗪杂环被证明是一个关键的功能基团，对于高活性和 P450 选择性至关重要。苯环取代对于降低清除率和获得良好的口服暴露非常重要。基于该先导化合物的优化工作，1-[4-甲基-6-(甲氨基)-1,3,5-三嗪-2-基]-N-[[4-溴-2-(三氟甲氧基)]-苯基]甲基]-4-哌啶甲酰胺（27）被鉴定为一种用于体内研究的有用的工具化合物。对血清生物标志物 9,10-环氧十八碳-12(Z)-烯酸（来源于亚油酸的环氧化物）的显著作用进行了观察，这为体内靶标结合的稳健性提供了证据，并证明 27 适合作为研究各种疾病模型的工具化合物。
