Medicinal Chemistry, Research and Early Development, Oncology R&D, AstraZeneca, Boston, 35 Gatehouse Drive, Waltham, MA 02451, United States.
Discovery Sciences, R&D, AstraZeneca, Gothenburg, SE-431 83 Mölndal, Sweden.
Bioorg Med Chem. 2020 Dec 1;28(23):115815. doi: 10.1016/j.bmc.2020.115815. Epub 2020 Oct 15.
In this article, we report our efforts towards improving in vitro human clearance in a series of 5-azaquinazolines through a series of C4 truncations and C2 expansions. Extensive DMPK studies enabled us to tackle high Aldehyde Oxidase (AO) metabolism and unexpected discrepancies in human hepatocyte and liver microsomal intrinsic clearance. Our efforts culminated with the discovery of 5-azaquinazoline 35, which also displayed exquisite selectivity for IRAK4, and showed synergistic in vitro activity against MyD88/CD79 double mutant ABC-DLBCL in combination with the covalent BTK inhibitor acalabrutinib.
在本文中，我们通过一系列的 C4 截断和 C2 扩展来报告我们在一系列 5-氮杂喹唑啉类化合物中提高体外人清除率的努力。广泛的 DMPK 研究使我们能够解决高醛氧化酶 (AO) 代谢和人肝细胞和肝微粒体内在清除率中的意外差异。我们的努力最终发现了 5-氮杂喹唑啉 35，它对 IRAK4 也具有极好的选择性，并与共价 BTK 抑制剂阿卡替尼联合使用时，对 MyD88/CD79 双突变 ABC-DLBCL 表现出协同的体外活性。
