Clemens Schöpf-Institute of Chemistry and Biochemistry, Technische Universität Darmstadt, Petersenstr. 22, Darmstadt D-64287, Germany.
Bioorg Med Chem. 2011 Aug 15;19(16):4903-9. doi: 10.1016/j.bmc.2011.06.062. Epub 2011 Jun 29.
Modulation of γ-secretase activity holds potential for the treatment of Alzheimer's disease. Most NSAID-derived γ-secretase modulators feature a carboxylic acid, which may impair blood-brain barrier permeation. The structure activity relationship of 33 carbazoles featuring diverse carboxylic acid isosteres or metabolic precursors thereof was established in a cellular amyloid secretion assay. The modulatory activity was observed for acidic moieties and metabolically labile esters only, which supports our hypothesis of an acid-lysine interaction to be relevant for this type of γ-secretase modulators.
γ-分泌酶活性的调节可能为阿尔茨海默病的治疗提供新的方法。大多数非甾体抗炎药（NSAID）衍生的γ-分泌酶调节剂都具有羧酸结构，这可能会损害血脑屏障的通透性。本文建立了 33 个咔唑类化合物的结构活性关系，这些化合物具有不同的羧酸类似物或其代谢前体，其在细胞淀粉样蛋白分泌试验中具有调节活性，仅酸性部分和代谢不稳定的酯具有调节活性，这支持了我们的假设，即酸-赖氨酸相互作用与这类γ-分泌酶调节剂有关。
