Department of Chemistry Research and Discovery, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA.
Bioorg Med Chem Lett. 2012 Jan 15;22(2):1226-9. doi: 10.1016/j.bmcl.2011.11.067. Epub 2011 Nov 23.
Structure-activity relationship (SAR) investigations of a novel class of triazolopyridazinone p38α mitogen activated protein kinase (MAPK) inhibitors are disclosed. From these studies, increased in vitro potency was observed for 2,6-disubstituted phenyl moieties and N-ethyl triazolopyridazinone cores due to key contacts with Leu108, Ala157 and Val38. Further investigation led to the identification of three compounds, 3g, 3j and 3m that are highly potent inhibitors of LPS-induced MAPKAP kinase 2 (MK2) phosphorylation in 50% human whole blood (hWB), and possess desirable in vivo pharmacokinetic and kinase selectivity profiles.
本研究揭示了新型三唑并哒嗪酮 p38α 丝裂原活化蛋白激酶（MAPK）抑制剂的构效关系（SAR）研究。通过这些研究，观察到 2,6-取代苯基部分和 N-乙基三唑并哒嗪酮核心由于与 Leu108、Ala157 和 Val38 的关键接触，体外活性增强。进一步的研究导致了三种化合物 3g、3j 和 3m 的鉴定，它们是脂多糖诱导的 MAPKAP 激酶 2（MK2）在 50%人全血（hWB）中的磷酸化的高活性抑制剂，并且具有理想的体内药代动力学和激酶选择性特征。
