PKI-179：一种口服有效的双磷脂酰肌醇-3-激酶（PI3K）/雷帕霉素靶蛋白（mTOR）抑制剂。
PKI-179: an orally efficacious dual phosphatidylinositol-3-kinase (PI3K)/mammalian target of rapamycin (mTOR) inhibitor.
机构信息
Chemical Sciences, PGRD, Pfizer Inc, Legacy Wyeth Research, 401 N. Middletown Rd, Pearl River, NY 10965, USA.
出版信息
Bioorg Med Chem Lett. 2010 Oct 1;20(19):5869-73. doi: 10.1016/j.bmcl.2010.07.104. Epub 2010 Jul 30.
A series of mono-morpholino 1,3,5-triazine derivatives (8a-8q) bearing a 3-oxa-8-azabicyclo[3.2.1]octane were prepared and evaluated for PI3-kinase/mTOR activity. Replacement of one of the bis-morpholines in lead compound 1 (PKI-587) with 3-oxa-8-azabicyclo[3.2.1]octane and reduction of the molecular weight yielded 8m (PKI-179), an orally efficacious dual PI3-kinase/mTOR inhibitor. The in vitro activity, in vivo efficacy, and PK properties of 8m are discussed.
一系列含有 3-氧代-8-氮杂双环[3.2.1]辛烷的单吗啉 1,3,5-三嗪衍生物（8a-8q）被制备并评估了它们对 PI3-激酶/mTOR 的活性。在先导化合物 1（PKI-587）中用 3-氧代-8-氮杂双环[3.2.1]辛烷替代一个双吗啉，并降低分子量，得到了具有口服活性的双重 PI3-激酶/mTOR 抑制剂 8m（PKI-179）。讨论了 8m 的体外活性、体内疗效和 PK 性质。
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