Clemens Schöpf-Institute of Chemistry and Biochemistry, Technische Universität Darmstadt, Petersenstr. 22, D-64287 Darmstadt, Germany.
Bioorg Med Chem Lett. 2009 Dec 15;19(24):6986-90. doi: 10.1016/j.bmcl.2009.10.035. Epub 2009 Oct 13.
Selective lowering of Abeta(42) levels with small-molecule substrate targeting gamma-secretase modulators (sGSMs), such as some non-steroidal anti-inflammatory drugs, is a promising therapeutic approach for Alzheimer's disease. Here we present N-substituted carbazole- and O-substituted fenofibrate-derived sGSMs and their activity data. Seven out of 19 screened compounds exhibited promising activity against Abeta(42) secretion at a low micromolar level. We presume that the sGSMs interact with lys624 at the membrane interface and that the lipophilic substituents anchor the compound orientation in the membrane.
使用小分子底物靶向 γ-分泌酶调节剂（sGSMs）选择性降低 Abeta(42)水平，如一些非甾体抗炎药，是治疗阿尔茨海默病的一种有前途的方法。在这里，我们介绍了 N-取代咔唑和 O-取代非诺贝特衍生的 sGSMs 及其活性数据。在低微摩尔水平下，筛选出的 19 种化合物中有 7 种对 Abeta(42)分泌表现出有希望的活性。我们推测 sGSMs 与膜界面上的 lys624 相互作用，并且亲脂性取代基将化合物的取向锚定在膜中。
