Chemical Sciences, Wyeth Research, 401 N. Middletown Road, Pearl River, NY 10965, USA.
Eur J Med Chem. 2010 Apr;45(4):1379-86. doi: 10.1016/j.ejmech.2009.12.036. Epub 2009 Dec 28.
A series of 8,9-dimethoxy-5-(2-aminoalkoxy-pyridin-3-yl)-benzo[c][2,7]naphthyridin-4-ylamine-based inhibitors of 3-phosphoinositide-dependent kinase-1 (PDK-1) has been identified. Several examples appear to be potent and relatively selective inhibitors of PDK-1 over the related AGC kinases PKA, PKB/AKT, and p70S6K. The introduction of a stereochemical center beside the amino substituent on the aminoalkoxy-side chain had little effect upon the inhibitory activity against these enzymes, and X-ray crystallographic analyses of a representative pair of enantiomeric inhibitors bound to the active site of PDK-1 revealed comparable binding modes for each enantiomer.
已经鉴定出一系列基于 8,9-二甲氧基-5-(2-氨氧基-吡啶-3-基)-苯并[c][2,7]萘啶-4-基胺的 3-磷酸肌醇依赖性激酶-1 (PDK-1)抑制剂。有几个例子似乎是 PDK-1 的有效且相对选择性抑制剂，对相关的 AGC 激酶 PKA、PKB/AKT 和 p70S6K 具有较高的选择性。在氨基烷氧基侧链上的氨基取代基旁边引入一个立体化学中心对这些酶的抑制活性几乎没有影响，并且代表一对与 PDK-1 活性位点结合的对映体抑制剂的 X 射线晶体学分析揭示了每个对映体的相似结合模式。
