Hu Carol H, Wang Tammy C, Qiao Jennifer X, Haque Lauren, Chen Alice Y A, Taylor David S, Ying Xiaohong, Onorato Joelle M, Galella Michael, Shen Hong, Huang Christine S, Toussaint Nathalie, Li Yi-Xin, Abell Lynn, Adam Leonard P, Gordon David, Wexler Ruth R, Finlay Heather J
Research and Development, Bristol-Myers Squibb, Princeton, NJ 08543, United States.
Research and Development, Bristol-Myers Squibb, Princeton, NJ 08543, United States.
Bioorg Med Chem Lett. 2018 Dec 15;28(23-24):3721-3725. doi: 10.1016/j.bmcl.2018.10.022. Epub 2018 Oct 15.
Endothelial lipase (EL) inhibitors have been shown to elevate HDL-C levels in pre-clinical murine models and have potential benefit in prevention and treatment of cardiovascular diseases. Modification of the 1-ethyl-3-hydroxy-1,5-dihydro-2H-pyrrol-2-one (DHP) lead, 1, led to the discovery of a series of potent tetrahydropyrimidinedione (THP) EL inhibitors. Synthesis and SAR studies including modification of the amide group, together with changes on the pyrimidinone core led to a series of arylcycloalkyl, indanyl, and tetralinyl substituted 5-amino or 5-hydroxypyrimidinedione-4-carboxamides. Several compounds were advanced to PK evaluation. Among them, compound 4a was one of the most potent with measurable EL hSerum potency and compound 3g demonstrated the best overall pharmacokinetic parameters.
内皮脂肪酶（EL）抑制剂已在临床前小鼠模型中显示出可提高高密度脂蛋白胆固醇（HDL-C）水平，并且在心血管疾病的预防和治疗中具有潜在益处。对1-乙基-3-羟基-1,5-二氢-2H-吡咯-2-酮（DHP）先导化合物1进行修饰，从而发现了一系列有效的四氢嘧啶二酮（THP）EL抑制剂。包括酰胺基团修饰在内的合成及构效关系（SAR）研究，以及嘧啶酮核心结构的变化，产生了一系列芳基环烷基、茚满基和四氢萘基取代的5-氨基或5-羟基嘧啶二酮-4-甲酰胺。几种化合物进入了药代动力学（PK）评估阶段。其中，化合物4a是效力最强的化合物之一，具有可测量的EL血清效力，而化合物3g表现出最佳的整体药代动力学参数。
