Flesch Daniel, Ness Julia, Lamers Christina, Dehm Friederike, Popella Sven, Steri Ramona, Ogorek Isabella, Hieke Martina, Dannhardt Gerd, Werz Oliver, Weggen Sascha, Schubert-Zsilavecz Manfred
Institute of Pharmaceutical Chemistry, Goethe-University Frankfurt, Max-von-Laue-Str. 9, D-60438 Frankfurt am Main, Germany.
Department of Neuropathology, Heinrich-Heine-University Düsseldorf, Moorenstrasse 5, D-40225 Düsseldorf, Germany.
Bioorg Med Chem Lett. 2015 Feb 15;25(4):841-6. doi: 10.1016/j.bmcl.2014.12.073. Epub 2014 Dec 30.
We present the design, synthesis and biological evaluation of compounds containing a 2-(benzylidene)hexanoic acid scaffold as multi-target directed γ-secretase-modulators. Broad structural variations were undertaken to elucidate the structure-activity-relationships at the 5-position of the aromatic core. Compound 13 showed the most potent activity profile with IC50 values of 0.79μM (Aβ42), 0.3μM (5-lipoxygenase) and an EC50 value of 4.64μM for PPARγ-activation. This derivative is the first compound exhibiting low micromolar to nanomolar activities for these three targets. Combining γ-secretase-modulation, PPARγ-agonism and inhibition of 5-lipoxygenase in one compound could be a novel disease-modifying multi-target-strategy for Alzheimer's disease to concurrently address the causative amyloid pathology and secondary pathologies like chronic brain inflammation.
我们展示了含有2-(亚苄基)己酸支架的化合物作为多靶点定向γ-分泌酶调节剂的设计、合成及生物学评价。进行了广泛的结构变化以阐明芳香核5位的构效关系。化合物13表现出最有效的活性谱，其对Aβ42的IC50值为0.79μM，对5-脂氧合酶的IC50值为0.3μM，对PPARγ激活的EC50值为4.64μM。该衍生物是首个对这三个靶点表现出低微摩尔至纳摩尔活性的化合物。在一种化合物中结合γ-分泌酶调节、PPARγ激动作用和5-脂氧合酶抑制作用，可能是一种用于阿尔茨海默病的新型疾病修饰多靶点策略，可同时解决致病性淀粉样蛋白病理和慢性脑炎症等继发性病理问题。
