Nizi Emanuela, Orsale Maria Vittoria, Crescenzi Benedetta, Pescatore Giovanna, Muraglia Ester, Alfieri Anna, Gardelli Cristina, Spieser Stéphane A H, Summa Vincenzo
Department of Medicinal Chemistry, IRBM-Merck Research Laboratories Rome, Pomezia, Italy.
Bioorg Med Chem Lett. 2009 Aug 15;19(16):4617-21. doi: 10.1016/j.bmcl.2009.06.091. Epub 2009 Jun 27.
In the context of HIV-integrase, dihydroxypyrimidine and N-methyl pyrimidone inhibitors the cellular activity of this class of compounds has been optimized by the introduction of a simple methyl substituent in the alpha-position of the C-2 side chains. Enhanced passive membrane permeability has been identified as the key factor driving the observed cell-based activity improvement. The rat PK profile of the alpha-methyl derivative 26a was also improved over its des-methyl exact analog.
在HIV整合酶、二羟基嘧啶和N-甲基嘧啶酮抑制剂的背景下，通过在C-2侧链的α位引入一个简单的甲基取代基，这类化合物的细胞活性得到了优化。增强的被动膜通透性已被确定为推动观察到的基于细胞的活性改善的关键因素。α-甲基衍生物26a的大鼠药代动力学特征也比其去甲基精确类似物有所改善。
