Terstiege Ina, Perry Matthew, Petersen Jens, Tyrchan Christian, Svensson Tor, Lindmark Helena, Öster Linda
Respiratory, Inflammation & Autoimmunity, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Pepparedsleden 1, Mölndal, 43183, Sweden.
Respiratory, Inflammation & Autoimmunity, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Pepparedsleden 1, Mölndal, 43183, Sweden.
Bioorg Med Chem Lett. 2017 Feb 1;27(3):679-687. doi: 10.1016/j.bmcl.2016.11.004. Epub 2016 Nov 2.
A novel class of potent PI3Kδ inhibitors with >1000-fold selectivity against other class I PI3K isoforms is described. Optimization of the substituents on a triazole aminopyrazine scaffold, emerging from an in-house PI3Kα program, turned moderately selective PI3Kδ compounds into highly potent and selective PI3Kδ inhibitors. These efforts resulted in a series of aminopyrazines with PI3Kδ IC⩽1nM in the enzyme assay, some of the most selective PI3Kδ inhibitors published to date, with a cell potency in a JeKo-cell assay of 20-120nM.
本文描述了一类新型的强效PI3Kδ抑制剂，其对其他I类PI3K亚型具有超过1000倍的选择性。对源自内部PI3Kα项目的三唑氨基吡嗪支架上的取代基进行优化，将中等选择性的PI3Kδ化合物转变为高效且选择性的PI3Kδ抑制剂。这些努力产生了一系列在酶测定中PI3Kδ IC⩽1nM的氨基吡嗪，它们是迄今为止报道的一些最具选择性的PI3Kδ抑制剂，在JeKo细胞测定中的细胞效力为20 - 120nM。
