Medicinal Chemistry, Pfizer, 401 N. Middletown Rd., Pearl River, NY 10965, USA.
Bioorg Med Chem Lett. 2011 Aug 15;21(16):4773-8. doi: 10.1016/j.bmcl.2011.06.063. Epub 2011 Jun 21.
We recently described several highly potent, triazine (1) and triazolopyrimidine (2) scaffold-based, dual PI3K/mTOR-inhibitors (e.g., 1, PKI-587) that were efficacious in both in vitro and in vivo models. In order to further optimize these compounds we devised a novel series, the 2-oxatriazines, which also exhibited excellent potency and good metabolic stability. Some 2-oxatriazines showed promising in vivo biomarker suppression and induced apoptosis in the MDA-MB-361 breast cancer xenograft model.
我们最近描述了几种高效的、基于三嗪（1）和三唑并嘧啶（2）支架的、双重 PI3K/mTOR 抑制剂（例如 1，PKI-587），它们在体外和体内模型中都有效。为了进一步优化这些化合物，我们设计了一个新系列，即 2-噁嗪，它们也表现出优异的效力和良好的代谢稳定性。一些 2-噁嗪在 MDA-MB-361 乳腺癌异种移植模型中显示出有希望的体内生物标志物抑制和诱导细胞凋亡的作用。
