Asberom Theodros, Zhao Zhiqiang, Bara Thomas A, Clader John W, Greenlee William J, Hyde Lynn A, Josien Hubert B, Li Wei, McPhail Andrew T, Nomeir Amin A, Parker Eric M, Rajagopalan Murali, Song Lixin, Wong Gwendolyn T, Zhang Lili, Zhang Qi, Pissarnitski Dmitri A
Department of Chemical Research, Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.
Bioorg Med Chem Lett. 2007 Jan 15;17(2):511-6. doi: 10.1016/j.bmcl.2006.10.011. Epub 2006 Oct 10.
Attachment of the cyclopropylcarbamate group to the piperidine core of gamma-secretase inhibitors leads to a dramatic increase of their in vitro potency. Strategies for subsequent improvement of the in vivo pharmacokinetic profile of the series are discussed. Resulting compounds significantly reduce Abeta levels in TgCRND8 mice after a single PO dosing at 30 mpk.
将环丙基氨基甲酸酯基团连接到γ-分泌酶抑制剂的哌啶核心上会导致其体外效力显著提高。讨论了该系列化合物随后改善体内药代动力学特征的策略。所得化合物在以30mg/kg的剂量单次口服给药后，可显著降低TgCRND8小鼠脑中的β-淀粉样蛋白（Aβ）水平。
