Thompson Lorin A, Liauw Ann Y, Ramanjulu Mercy M, Kasireddy-Polam Padmaja, Mercer Stephen E, Maduskuie Thomas P, Glicksman Marcie, Roach Arthur H, Meredith Jere E, Liu Rui-Qin, Combs Andrew P, Higaki Jeffrey N, Cordell Barbara, Seiffert Dietmar, Zaczek Robert C, Robertson David W, Olson Richard E
Bristol-Myers Squibb Pharmaceutical Research Institute, 5 Research Parkway, Wallingford, CT 06492, USA.
Bioorg Med Chem Lett. 2006 May 1;16(9):2357-63. doi: 10.1016/j.bmcl.2006.01.055. Epub 2006 Feb 10.
The synthesis, evaluation, and structure-activity relationships of a series of succinoyl lactam inhibitors of the Alzheimer's disease gamma-secretase are described. Beginning with a screening hit with broad proteinase activity, optimization provided compounds with both high selectivity for inhibition of gamma-secretase and high potency in cellular assays of A beta reduction. The SAR and early in vivo properties of this series of inhibitors will be presented.
本文描述了一系列用于治疗阿尔茨海默病的γ-分泌酶的琥珀酰内酰胺抑制剂的合成、评估及其构效关系。从具有广泛蛋白酶活性的筛选命中物开始，通过优化得到了对γ-分泌酶抑制具有高选择性且在细胞实验中降低β-淀粉样蛋白（Aβ）水平方面具有高效能的化合物。将介绍该系列抑制剂的构效关系及早期体内性质。
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