Neurosciences Centre of Excellence for Drug Discovery, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, UK.
Bioorg Med Chem Lett. 2010 Feb 1;20(3):1306-11. doi: 10.1016/j.bmcl.2009.08.072. Epub 2009 Aug 23.
This Letter details the SAR of a novel series of piperidine-derived gamma-secretase modulators. Compound 10h was found to be a potent modulator in vitro, which on further profiling, was found to decrease Abeta42, increase Abeta38 and have no effect on Abeta40 levels. Furthermore, 10h demonstrated excellent pharmacokinetic parameters in the mouse, rat and dog in addition to good CNS penetration in the mouse.
这封信详细说明了一系列新型哌啶衍生γ-分泌酶调节剂的 SAR。发现化合物 10h 是一种有效的体外调节剂，进一步研究发现，它可以降低 Abeta42，增加 Abeta38，对 Abeta40 水平没有影响。此外，10h 在小鼠、大鼠和犬中表现出优异的药代动力学参数，并且在小鼠中具有良好的中枢神经系统穿透性。
